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Wang SY, Huang ZH, Duan R, Fu XX, Qi JW, Luo ZJ, Zhang YD, Jiang T. IL-34/TREM2 modulates microglia-mediated inflammation and provides neuroprotection in a mouse model of sporadic Alzheimer's disease. J Alzheimers Dis 2025; 104:875-885. [PMID: 40025720 DOI: 10.1177/13872877251320418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
BackgroundAs a recently identified cytokine, interleukin-34 (IL-34) is predominantly produced by neurons and functions as a modulator for glial functions. Emerging evidence indicates that IL-34 exerted neuroprotective effects in Alzheimer's disease (AD), but the underlying mechanism remained elusive.ObjectiveTo uncover the mechanisms by which IL-34 provides neuroprotection in AD.MethodsUsing senescence-accelerated mouse prone substrain 8 (SAMP8) mice, a well-established model for sporadic AD, we investigated the dynamic changes in brain IL-34 concentrations during AD progression. Afterwards, SAMP8 mice received a 4-week continuous intracerebroventricular infusion of IL-34. Morris water maze test was employed to assess the spatial cognitive functions. Neuronal and synaptic markers, oxidative stress makers, pro-inflammatory cytokines and glial activation markers in the brains of SAMP8 mice were measured. Finally, amyloid-β (Aβ)42-stimulated primary microglia, lentivirus-mediated gene knockdown strategy and co-immunoprecipitation assay were utilized to uncover the possible mechanisms by which IL-34 exerted neuroprotection in AD.ResultsIn SAMP8 mice, we revealed that brain IL-34 concentrations gradually decreased during AD progression. A 4-week continuous intracerebroventricular infusion of IL-34 rescued spatial cognitive impairments, ameliorated neuronal and synaptic damage, and suppressed oxidative stress and microglia-mediated inflammation in the brains of SAMP8 mice. Using Aβ42-stimulated primary microglia, we demonstrated for the first time that IL-34 suppressed microglial NLRP3 inflammasome activation and pro-inflammatory cytokines release by interacting with triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial functions.ConclusionsThese findings uncover the mechanisms by which IL-34 provides neuroprotection in AD, indicating that IL-34/TREM2 signaling may represent a novel therapeutic strategy for this devastating disease.
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Affiliation(s)
- Shi-Yao Wang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Zhi-Hang Huang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Rui Duan
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Xin-Xin Fu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Jing-Wen Qi
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Zi-Jian Luo
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Ying-Dong Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, PR China
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2
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Leach LL, Gonzalez RG, Jayawardena SU, Gross JM. Interleukin-34 and debris clearance by mononuclear phagocytes drive retinal pigment epithelium regeneration in zebrafish. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.10.632236. [PMID: 39868193 PMCID: PMC11761032 DOI: 10.1101/2025.01.10.632236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
The retinal pigment epithelium (RPE) surrounds the posterior eye and maintains the health and function of the photoreceptors. Consequently, RPE dysfunction or damage has a devastating impact on vision. Due to complex etiologies, there are currently no cures for patients with RPE degenerative diseases, which remain some of the most prevalent causes of vision loss worldwide. Further, owing to a limited capacity for mammalian tissue repair, we know little about how the RPE regenerates. Here, we utilize zebrafish as a model to uncover novel mechanisms driving intrinsic RPE regeneration. We show that interleukin-34 signaling from damaged RPE is required for precisely timed recruitment of mononuclear phagocytes (MNPs) to the injury site. Additionally, we find that cellular debris clearance by MNPs is indispensable for regeneration, as microglia-deficient zebrafish fail to regenerate RPE and photoreceptor tissues. Together, our results establish specific pro-regenerative functions of MNPs after RPE damage.
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Affiliation(s)
- Lyndsay L. Leach
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, United States of America
| | - Rebecca G. Gonzalez
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, United States of America
| | - Sayuri U. Jayawardena
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, United States of America
| | - Jeffrey M. Gross
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, United States of America
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3
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Ueno H, Hattori T, Chi HH, Miyabe Y, Murayama MA. Clodronate liposome treatment contributes to the nerve regeneration in corneal nerve involvement of diabetic mice. Exp Anim 2025; 74:58-65. [PMID: 39111878 PMCID: PMC11742477 DOI: 10.1538/expanim.24-0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 07/31/2024] [Indexed: 01/15/2025] Open
Abstract
The dense nerve and thin vascular structure of the corneal tissue provide the refractive function in healthy eyes. Diabetes mellitus causes ocular complications including corneal opacification because of corneal nerve degeneration. Diabetic neurotrophic keratopathy is characterized by reduced corneal sensitivity, delayed corneal wound healing, and nerve degeneration. Neurotization and vascularization inhibit each other in the cornea. Macrophages contribute to the corneal neovascularization. To investigate the role of macrophage in neurotrophic keratopathy, clodronate liposome was subconjunctivally injected into diabetic db/db mice with neurotrophic keratopathy. The clodronate liposome treatment decreased F4/80+ macrophage infiltration into the corneal epithelium, and improved corneal nerve involvement in diabetic db/db mice. Furthermore, we found that Il1b and Il34 mRNA expression was increased in the corneal epithelium of clodronate-treated diabetic db/db mice. These cytokines contribute to the maintenance of nerve tissues via microglia and nerve regeneration; however, their role in corneal nerve involvement remains unknown. Notably, the intraocular injection of recombinant IL-1β and IL-34 promoted nerve regeneration in the cornea of diabetic db/db mice. These results suggest that clodronate liposome treatment contributes to nerve regeneration during corneal involvement via IL-1β and IL-34 signaling.
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Affiliation(s)
- Hiroki Ueno
- Department of Immunology and Parasitology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan
| | - Takaaki Hattori
- Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Hsi-Hua Chi
- Department of Animal Models for Human Diseases, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan
| | - Yoshishige Miyabe
- Department of Immunology and Parasitology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan
| | - Masanori A Murayama
- Department of Animal Models for Human Diseases, Institute of Biomedical Science, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan
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4
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Wiens KR, Wasti N, Ulloa OO, Klegeris A. Diversity of Microglia-Derived Molecules with Neurotrophic Properties That Support Neurons in the Central Nervous System and Other Tissues. Molecules 2024; 29:5525. [PMID: 39683685 DOI: 10.3390/molecules29235525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Microglia, the brain immune cells, support neurons by producing several established neurotrophic molecules including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Modern analytical techniques have identified numerous phenotypic states of microglia, each associated with the secretion of a diverse set of substances, which likely include not only canonical neurotrophic factors but also other less-studied molecules that can interact with neurons and provide trophic support. In this review, we consider the following eight such candidate cytokines: oncostatin M (OSM), leukemia inhibitory factor (LIF), activin A, colony-stimulating factor (CSF)-1, interleukin (IL)-34, growth/differentiation factor (GDF)-15, fibroblast growth factor (FGF)-2, and insulin-like growth factor (IGF)-2. The available literature provides sufficient evidence demonstrating murine cells produce these cytokines and that they exhibit neurotrophic activity in at least one neuronal model. Several distinct types of neurotrophic activity are identified that only partially overlap among the cytokines considered, reflecting either their distinct intrinsic properties or lack of comprehensive studies covering the full spectrum of neurotrophic effects. The scarcity of human-specific studies is another significant knowledge gap revealed by this review. Further studies on these potential microglia-derived neurotrophic factors are warranted since they may be used as targeted treatments for diverse neurological disorders.
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Affiliation(s)
- Kennedy R Wiens
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Naved Wasti
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Omar Orlando Ulloa
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Andis Klegeris
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
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5
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Ruisch IH, Widomska J, De Witte W, Mota NR, Fanelli G, Van Gils V, Jansen WJ, Vos SJB, Fóthi A, Barta C, Berkel S, Alam KA, Martinez A, Haavik J, O'Leary A, Slattery D, Sullivan M, Glennon J, Buitelaar JK, Bralten J, Franke B, Poelmans G. Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases. Alzheimers Res Ther 2024; 16:239. [PMID: 39465382 PMCID: PMC11514822 DOI: 10.1186/s13195-024-01609-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 10/21/2024] [Indexed: 10/29/2024]
Abstract
Alzheimer's disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards "energy metabolism" as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.
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Affiliation(s)
- I Hyun Ruisch
- Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joanna Widomska
- Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ward De Witte
- Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nina R Mota
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Giuseppe Fanelli
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Veerle Van Gils
- Department of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Willemijn J Jansen
- Department of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Stephanie J B Vos
- Department of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Abel Fóthi
- Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Csaba Barta
- Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Simone Berkel
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Kazi A Alam
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Aurora Martinez
- Department of Biomedicine, University of Bergen, Bergen, Norway
- K.G. Jebsen Center for Translational Research in Parkinson's Disease, University of Bergen, Neuro-SysMed Center, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Jan Haavik
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Aet O'Leary
- Department of Psychiatry, University Hospital, Frankfurt, Germany
| | - David Slattery
- Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität, Frankfurt, Germany
| | - Mairéad Sullivan
- Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Jeffrey Glennon
- Conway Institute of Biomedical and Biomolecular Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Jan K Buitelaar
- Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Janita Bralten
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Barbara Franke
- Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
| | - Geert Poelmans
- Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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6
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Gunasekaran TI, Meena D, Lee AJ, Wu S, Dumitrescu L, Sperling R, Hohman TJ, Huang J, Dehghan A, Tzoulaki I, Mayeux R, Vardarajan B. Genome-wide scan of Flortaucipir PET levels finds JARID2 associated with cerebral tau deposition. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.10.04.24314853. [PMID: 39417126 PMCID: PMC11482994 DOI: 10.1101/2024.10.04.24314853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
BACKGROUND Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD. METHODS We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18]F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18]F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses. RESULTS GWAS of tau-SUVR revealed two significant loci: rs78636169 (P=5.76×10-10) in JARID2 and rs7292124 (P=2.20×10-8) near ISX. Gene-based analysis of tau deposition highlighted APOE (P=2.55×10-6), CTNNA3 (P=2.86×10-6) and JARID2 (P=1.23×10-4), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE-ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers. CONCLUSION We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.
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Affiliation(s)
- Tamil Iniyan Gunasekaran
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, USA
| | - Devendra Meena
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK
| | - Annie J Lee
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, USA
- Department of Neurology, The New York Presbyterian Hospital, New York, USA
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, USA
| | - Siwei Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK
| | - Logan Dumitrescu
- Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Reisa Sperling
- Department of Neurology, Massachusetts General Hospital, Boston, USA
- Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Timothy J Hohman
- Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jingxian Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK
- BHF Centre of Excellence, School of Public Health, Imperial College London, London, UK
- UK Dementia Research Institute, Imperial College London, London, UK
| | - Ioanna Tzoulaki
- Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, UK
| | - Richard Mayeux
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, USA
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, USA
| | - Badri Vardarajan
- The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, USA
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, USA
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, USA
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7
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Martin SP, Leeman-Markowski BA. Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer's disease, and epilepsy. Front Neurol 2024; 14:1287545. [PMID: 38249745 PMCID: PMC10797726 DOI: 10.3389/fneur.2023.1287545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/30/2023] [Indexed: 01/23/2024] Open
Abstract
Traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a "tipping point" hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a "last ditch effort" to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy.
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Affiliation(s)
- Samantha P. Martin
- Comprehensive Epilepsy Center, New York University Langone Health, New York, NY, United States
- Department of Neurology, New York University Langone Health, New York, NY, United States
- New York University Grossman School of Medicine, New York, NY, United States
- VA New York Harbor Healthcare System, New York, NY, United States
| | - Beth A. Leeman-Markowski
- Comprehensive Epilepsy Center, New York University Langone Health, New York, NY, United States
- Department of Neurology, New York University Langone Health, New York, NY, United States
- VA New York Harbor Healthcare System, New York, NY, United States
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8
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Bear RM, Caspary T. Uncovering cilia function in glial development. Ann Hum Genet 2024; 88:27-44. [PMID: 37427745 PMCID: PMC10776815 DOI: 10.1111/ahg.12519] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/14/2023] [Accepted: 06/19/2023] [Indexed: 07/11/2023]
Abstract
Primary cilia play critical roles in regulating signaling pathways that underlie several developmental processes. In the nervous system, cilia are known to regulate signals that guide neuron development. Cilia dysregulation is implicated in neurological diseases, and the underlying mechanisms remain poorly understood. Cilia research has predominantly focused on neurons and has overlooked the diverse population of glial cells in the brain. Glial cells play essential roles during neurodevelopment, and their dysfunction contributes to neurological disease; however, the relationship between cilia function and glial development is understudied. Here we review the state of the field and highlight the glial cell types where cilia are found and the ciliary functions that are linked to glial development. This work uncovers the importance of cilia in glial development and raises outstanding questions for the field. We are poised to make progress in understanding the function of glial cilia in human development and their contribution to neurological diseases.
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Affiliation(s)
- Rachel M. Bear
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta GA 30322
- Graduate Program in Neuroscience
| | - Tamara Caspary
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta GA 30322
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9
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Tijms BM, Vromen EM, Mjaavatten O, Holstege H, Reus LM, van der Lee S, Wesenhagen KEJ, Lorenzini L, Vermunt L, Venkatraghavan V, Tesi N, Tomassen J, den Braber A, Goossens J, Vanmechelen E, Barkhof F, Pijnenburg YAL, van der Flier WM, Teunissen CE, Berven FS, Visser PJ. Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles. NATURE AGING 2024; 4:33-47. [PMID: 38195725 PMCID: PMC10798889 DOI: 10.1038/s43587-023-00550-7] [Citation(s) in RCA: 66] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/29/2023] [Indexed: 01/11/2024]
Abstract
Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.
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Affiliation(s)
- Betty M Tijms
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
| | - Ellen M Vromen
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Olav Mjaavatten
- Proteomics Unit at the University of Bergen, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Henne Holstege
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
| | - Lianne M Reus
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sven van der Lee
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
| | - Kirsten E J Wesenhagen
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Luigi Lorenzini
- Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neuroimaging, Amsterdam, the Netherlands
| | - Lisa Vermunt
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Neurochemistry Laboratory, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
| | - Vikram Venkatraghavan
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Niccoló Tesi
- Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands
| | - Jori Tomassen
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Anouk den Braber
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | | | | | - Frederik Barkhof
- Department of Radiology and Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK
| | - Yolande A L Pijnenburg
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
| | - Wiesje M van der Flier
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Epidemiology & Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
| | - Charlotte E Teunissen
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Neurochemistry Laboratory, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
| | - Frode S Berven
- Proteomics Unit at the University of Bergen, Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Pieter Jelle Visser
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
- Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands
- Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
- Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
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10
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Li Y, Li YJ, Zhu ZQ. To re-examine the intersection of microglial activation and neuroinflammation in neurodegenerative diseases from the perspective of pyroptosis. Front Aging Neurosci 2023; 15:1284214. [PMID: 38020781 PMCID: PMC10665880 DOI: 10.3389/fnagi.2023.1284214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
Neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and motor neuron disease, are diseases characterized by neuronal damage and dysfunction. NDs are considered to be a multifactorial disease with diverse etiologies (immune, inflammatory, aging, genetic, etc.) and complex pathophysiological processes. Previous studies have found that neuroinflammation and typical microglial activation are important mechanisms of NDs, leading to neurological dysfunction and disease progression. Pyroptosis is a new mode involved in this process. As a form of programmed cell death, pyroptosis is characterized by the expansion of cells until the cell membrane bursts, resulting in the release of cell contents that activates a strong inflammatory response that promotes NDs by accelerating neuronal dysfunction and abnormal microglial activation. In this case, abnormally activated microglia release various pro-inflammatory factors, leading to the occurrence of neuroinflammation and exacerbating both microglial and neuronal pyroptosis, thus forming a vicious cycle. The recognition of the association between pyroptosis and microglia activation, as well as neuroinflammation, is of significant importance in understanding the pathogenesis of NDs and providing new targets and strategies for their prevention and treatment.
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Affiliation(s)
- Yuan Li
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- College of Anesthesiology, Zunyi Medical University, Zunyi, China
| | - Ying-Jie Li
- Department of General Surgery, Mianyang Hospital of Traditional Chinese Medicine, Mianyang, China
| | - Zhao-Qiong Zhu
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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11
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Shang J, Xu Y, Pu S, Sun X, Gao X. Role of IL-34 and its receptors in inflammatory diseases. Cytokine 2023; 171:156348. [PMID: 37683444 DOI: 10.1016/j.cyto.2023.156348] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023]
Abstract
In recent years, IL-34 has been widely discussed as a novel cytokine. IL-34 is a pro-inflammatory cytokine binding four distinct receptors, namely CSF-1R, syndecan-1, PTP-ζ and TREM2. Previous studies have shown that IL-34 and its receptors play important roles in the development and progression of various inflammatory diseases. Therefore, IL-34 has the potential to be a biomarker and therapeutic target for inflammatory diseases. However, further study is still needed to identify the specific mechanism through which IL-34 contributes to illness. In this article, we review the recent advances in the biological roles of IL-34 and its receptors as well as their roles in the development and therapeutic application of inflammatory diseases.
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Affiliation(s)
- Jiameng Shang
- The First Affiliated Hospital of Harbin Medical University, People's Republic of China
| | - Yuxin Xu
- The First Affiliated Hospital of Harbin Medical University, People's Republic of China
| | - Shengdan Pu
- The First Affiliated Hospital of Harbin Medical University, People's Republic of China
| | - Xiaotong Sun
- The First Affiliated Hospital of Harbin Medical University, People's Republic of China
| | - Xinyuan Gao
- The First Affiliated Hospital of Harbin Medical University, People's Republic of China.
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12
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Bettag J, Goldenberg D, Carter J, Morfin S, Borsotti A, Fox J, ReVeal M, Natrop D, Gosser D, Kolli S, Jain AK. Gut Microbiota to Microglia: Microbiome Influences Neurodevelopment in the CNS. CHILDREN (BASEL, SWITZERLAND) 2023; 10:1767. [PMID: 38002858 PMCID: PMC10670365 DOI: 10.3390/children10111767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/19/2023] [Accepted: 10/28/2023] [Indexed: 11/26/2023]
Abstract
The brain is traditionally viewed as an immunologically privileged site; however, there are known to be multiple resident immune cells that influence the CNS environment and are reactive to extra-CNS signaling. Microglia are an important component of this system, which influences early neurodevelopment in addition to modulating inflammation and regenerative responses to injury and infection. Microglia are influenced by gut microbiome-derived metabolites, both as part of their normal function and potentially in pathological patterns that may induce neurodevelopmental disabilities or behavioral changes. This review aims to summarize the mounting evidence indicating that, not only is the Gut-Brain axis mediated by metabolites and microglia throughout an organism's lifetime, but it is also influenced prenatally by maternal microbiome and diet, which holds implications for both early neuropathology and neurodevelopment.
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Affiliation(s)
- Jeffery Bettag
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Daniel Goldenberg
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Jasmine Carter
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Sylvia Morfin
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Alison Borsotti
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - James Fox
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Matthew ReVeal
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Dylan Natrop
- Medical College of Wisconsin-Green Bay, De Pere, WI 54115, USA;
| | - David Gosser
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Sree Kolli
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
| | - Ajay K. Jain
- Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO 63103, USA; (D.G.); (J.C.); (S.M.); (A.B.); (J.F.); (M.R.); (D.G.); (S.K.); (A.K.J.)
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13
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Garrido-Martín D, Calvo M, Reverter F, Guigó R. A fast non-parametric test of association for multiple traits. Genome Biol 2023; 24:230. [PMID: 37828616 PMCID: PMC10571397 DOI: 10.1186/s13059-023-03076-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 09/27/2023] [Indexed: 10/14/2023] Open
Abstract
The increasing availability of multidimensional phenotypic data in large cohorts of genotyped individuals requires efficient methods to identify genetic effects on multiple traits. Permutational multivariate analysis of variance (PERMANOVA) offers a powerful non-parametric approach. However, it relies on permutations to assess significance, which hinders the analysis of large datasets. Here, we derive the limiting null distribution of the PERMANOVA test statistic, providing a framework for the fast computation of asymptotic p values. Our asymptotic test presents controlled type I error and high power, often outperforming parametric approaches. We illustrate its applicability in the context of QTL mapping and GWAS.
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Affiliation(s)
- Diego Garrido-Martín
- Department of Genetics, Microbiology and Statistics, Universitat de Barcelona (UB), Av. Diagonal 643, Barcelona, 08028, Spain.
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Catalonia, Spain.
| | - Miquel Calvo
- Department of Genetics, Microbiology and Statistics, Universitat de Barcelona (UB), Av. Diagonal 643, Barcelona, 08028, Spain
| | - Ferran Reverter
- Department of Genetics, Microbiology and Statistics, Universitat de Barcelona (UB), Av. Diagonal 643, Barcelona, 08028, Spain
| | - Roderic Guigó
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Catalonia, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain
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14
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Carvalho D, Diaz-Amarilla P, Dapueto R, Santi MD, Duarte P, Savio E, Engler H, Abin-Carriquiry JA, Arredondo F. Transcriptomic Analyses of Neurotoxic Astrocytes Derived from Adult Triple Transgenic Alzheimer's Disease Mice. J Mol Neurosci 2023; 73:487-515. [PMID: 37318736 DOI: 10.1007/s12031-023-02105-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/03/2023] [Indexed: 06/16/2023]
Abstract
Neurodegenerative diseases such as Alzheimer's disease have been classically studied from a purely neuronocentric point of view. More recent evidences support the notion that other cell populations are involved in disease progression. In this sense, the possible pathogenic role of glial cells like astrocytes is increasingly being recognized. Once faced with tissue damage signals and other stimuli present in disease environments, astrocytes suffer many morphological and functional changes, a process referred as reactive astrogliosis. Studies from murine models and humans suggest that these complex and heterogeneous responses could manifest as disease-specific astrocyte phenotypes. Clear understanding of disease-associated astrocytes is a necessary step to fully disclose neurodegenerative processes, aiding in the design of new therapeutic and diagnostic strategies. In this work, we present the transcriptomics characterization of neurotoxic astrocytic cultures isolated from adult symptomatic animals of the triple transgenic mouse model of Alzheimer's disease (3xTg-AD). According to the observed profile, 3xTg-AD neurotoxic astrocytes show various reactivity features including alteration of the extracellular matrix and release of pro-inflammatory and proliferative factors that could result in harmful effects to neurons. Moreover, these alterations could be a consequence of stress responses at the endoplasmic reticulum and mitochondria as well as of concomitant metabolic adaptations. Present results support the hypothesis that adaptive changes of astrocytic function induced by a stressed microenvironment could later promote harmful astrocyte phenotypes and further accelerate or induce neurodegenerative processes.
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Affiliation(s)
- Diego Carvalho
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay
| | - Pablo Diaz-Amarilla
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Rosina Dapueto
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - María Daniela Santi
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
- College of Dentistry, Bluestone Center for Clinical Research, New York University, New York, 10010, USA
| | - Pablo Duarte
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Eduardo Savio
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Henry Engler
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
- Facultad de Medicina, Universidad de la República, 1800, Montevideo, Uruguay
| | - Juan A Abin-Carriquiry
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
- Laboratorio de Biofármacos, Institut Pasteur de Montevideo, 11600, Montevideo, Uruguay.
| | - Florencia Arredondo
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay.
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15
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Cruchaga C, Western D, Timsina J, Wang L, Wang C, Yang C, Ali M, Beric A, Gorijala P, Kohlfeld P, Budde J, Levey A, Morris J, Perrin R, Ruiz A, Marquié M, Boada M, de Rojas I, Rutledge J, Oh H, Wilson E, Guen YL, Alvarez I, Aguilar M, Greicius M, Pastor P, Pulford D, Ibanez L, Wyss-Coray T, Sung YJ, Phillips B. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease. RESEARCH SQUARE 2023:rs.3.rs-2814616. [PMID: 37333337 PMCID: PMC10275048 DOI: 10.21203/rs.3.rs-2814616/v1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease-associated loci. QTL mapping has mainly been focused on multi-tissue expression QTL or plasma protein QTL (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs of which 1,585 are unique to CSF, demonstrating unique genetic regulation of the CSF proteome. In addition to the established chr6p22.2-21.32 HLA region, we identified pleiotropic regions on chr3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron-specificity and neurological development. We also integrated this pQTL atlas with the latest Alzheimer's disease (AD) GWAS through PWAS, colocalization and Mendelian Randomization and identified 42 putative causal proteins for AD, 15 of which have drugs available. Finally, we developed a proteomics-based risk score for AD that outperforms genetics-based polygenic risk scores. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.
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Affiliation(s)
| | - Dan Western
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Jigyasha Timsina
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Lihua Wang
- Washington University School of Medicine
| | | | | | | | | | | | - Patsy Kohlfeld
- Washington University School of Medicine, St Louis, MO, USA
| | | | | | | | | | | | | | - Mercè Boada
- Memory Clinic of Fundaciò ACE, Catalan Institute of Applied Neurosciences
| | | | | | | | | | | | - Ignacio Alvarez
- Fundació Docència i Recerca Mútua Terrassa, Terrassa, Barcelona, Spain
| | | | | | - Pau Pastor
- University Hospital Germans Trias i Pujol
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16
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Fujikawa R, Tsuda M. The Functions and Phenotypes of Microglia in Alzheimer's Disease. Cells 2023; 12:cells12081207. [PMID: 37190116 DOI: 10.3390/cells12081207] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/17/2023] [Accepted: 04/20/2023] [Indexed: 05/17/2023] Open
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, but therapeutic strategies to slow down AD pathology and symptoms have not yet been successful. While attention has been focused on neurodegeneration in AD pathogenesis, recent decades have provided evidence of the importance of microglia, and resident immune cells in the central nervous system. In addition, new technologies, including single-cell RNA sequencing, have revealed heterogeneous cell states of microglia in AD. In this review, we systematically summarize the microglial response to amyloid-β and tau tangles, and the risk factor genes expressed in microglia. Furthermore, we discuss the characteristics of protective microglia that appear during AD pathology and the relationship between AD and microglia-induced inflammation during chronic pain. Understanding the diverse roles of microglia will help identify new therapeutic strategies for AD.
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Affiliation(s)
- Risako Fujikawa
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Makoto Tsuda
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Kyushu University Institute for Advanced Study, Fukuoka 819-0395, Japan
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17
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Abstract
Alzheimer's disease (AD) is a debilitating age-related neurodegenerative condition. Unbiased genetic studies have implicated a central role for microglia, the resident innate immune cells of the central nervous system, in AD pathogenesis. On-going efforts are clarifying the biology underlying these associations and the microglial pathways that are dysfunctional in AD. Several genetic risk factors converge to decrease the function of activating microglial receptors and increase the function of inhibitory receptors, resulting in a seemingly dampened microglial phenotype in AD. Moreover, many of these microglial proteins that are genetically associated with AD appear to interact and share pathways or regulatory mechanisms, presenting several points of convergence that may be strategic targets for therapeutic intervention. Here, we review some of these studies and their implications for microglial participation in AD pathogenesis.
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18
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Ma J, Wu N, Yuan Z, Chen Y, Li C, Xie W, Zhang Z, Li Y, Zhong L. Prognostic value of interleukin-34 and interleukin-38 in patients with newly diagnosed atrial fibrillation. Front Cardiovasc Med 2023; 9:1072164. [PMID: 36698935 PMCID: PMC9868840 DOI: 10.3389/fcvm.2022.1072164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/22/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Interleukin (IL)-34 and IL-38 are associated with cardiovascular disease (CVD). However, their involvement in atrial fibrillation (AF) and AF-associated adverse events remains uncertain. Therefore, we aimed to investigate their association with various AF prognostic factors in a cohort study and assessed their predictive value for the prognosis of patients with AF. METHODS Patients with new-onset non-valvular AF were consecutively enrolled between 2013 and 2015 at the Department of Cardiovascular Medicine of the Southwest Hospital of the Army Medical University (Third Military Medical University) in Chongqing, China. The endpoints included stroke and all-cause mortality. The baseline levels of plasma IL-34, IL-38, NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and GDF-15 were measured and their correlation with AF-related adverse events were analyzed in a Cox proportional-hazards regression model. The C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the performance of the AF prognostic models. Decision curve analysis (DCA) was used to evaluate the clinical net benefit of the original and modified models. RESULTS A total of 299 patients with new-onset AF were enrolled. During the median follow-up time of 28 (IQR: 27, 29) months, the higher levels of IL-34 were associated with a lower risk of stroke, and the higher levels of IL-38 were associated with an increased risk of all-cause death (all adjusted P < 0.05). In addition, elevated hs-cTnT and NT-proBNP concentrations were associated with a higher risk of stroke and all-cause mortality (all adjusted P < 0.05). Furthermore, the CHA2DS2-VASc score combined with IL-38 and NT-proBNP significantly improved the C-statistic, IDI, and NRI (all P < 0.01). There was no statistically significant difference (all P > 0.05) in the discrimination power between the preference models and the ABC (age, biomarkers, and clinical history) score for the two prognostic outcomes. CONCLUSION Our results suggested that IL-34 and IL-38 were independently associated with stroke and all-cause mortality in patients with AF. Moreover, adding IL-38 and NT-proBNP to the CHA2DS2-VASc score significantly improved its predictive ability of AF-related all-cause death. Finally, the preference model performed equally well as the ABC score in predicting AF prognosis.
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Affiliation(s)
- Jiaxue Ma
- Cardiovascular Disease Center, Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Na Wu
- Department of Epidemiology, College of Preventive Medicine, Army Medical University, Chongqing, China
- Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University, Chongqing, China
| | - Zhiquan Yuan
- Department of Epidemiology, College of Preventive Medicine, Army Medical University, Chongqing, China
- Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University, Chongqing, China
| | - Yanxiu Chen
- Department of Cardiology, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing, China
| | - Chengying Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University, Chongqing, China
- Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University, Chongqing, China
| | - Weijia Xie
- Department of Epidemiology, College of Preventive Medicine, Army Medical University, Chongqing, China
- Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University, Chongqing, China
| | - Zhihui Zhang
- Department of Cardiology, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yafei Li
- Department of Epidemiology, College of Preventive Medicine, Army Medical University, Chongqing, China
- Evidence-based Medicine and Clinical Epidemiology Center, Army Medical University, Chongqing, China
| | - Li Zhong
- Cardiovascular Disease Center, Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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19
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Xiang C, Li H, Tang W. Targeting CSF-1R represents an effective strategy in modulating inflammatory diseases. Pharmacol Res 2023; 187:106566. [PMID: 36423789 DOI: 10.1016/j.phrs.2022.106566] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/12/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022]
Abstract
Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, is a type I single transmembrane protein mainly expressed in myeloid cells, such as monocytes, macrophages, glial cells, and osteoclasts. The endogenous ligands, colony-stimulating factor-1 (CSF-1) and Interleukin-34 (IL-34), activate CSF-1R and downstream signaling pathways including PI3K-AKT, JAK-STATs, and MAPKs, and modulate the proliferation, differentiation, migration, and activation of target immune cells. Over the past decades, the promising therapeutic potential of CSF-1R signaling inhibition has been widely studied for decreasing immune suppression and escape in tumors, owing to depletion and reprogramming of tumor-associated macrophages. In addition, the excessive activation of CSF-1R in inflammatory diseases is consecutively uncovered in recent years, which may result in inflammation in bone, kidney, lung, liver and central nervous system. Agents against CSF-1R signaling have been increasingly investigated in preclinical or clinical studies for inflammatory diseases treatment. However, the pathological mechanism of CSF-1R in inflammation is indistinct and whether CSF-1R signaling can be identified as biomarkers remains controversial. With the background information aforementioned, this review focus on the dialectical roles of CSF-1R and its ligands in regulating innate immune cells and highlights various therapeutic implications of blocking CSF-1R signaling in inflammatory diseases.
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Affiliation(s)
- Caigui Xiang
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Heng Li
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Wei Tang
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
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20
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Boruah P, Deka N. Interleukin 34 in Disease Progressions: A Comprehensive Review. Crit Rev Immunol 2023; 43:25-43. [PMID: 37943151 DOI: 10.1615/critrevimmunol.2023050326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
IL-34, a cytokine, discovered a decade before and is known to be a colony stimulating factor CSF-1 receptor (CSF-1R) ligand. Along with CSF-1R, it also interacts with syndecan-1 receptors and protein-tyrosine phosphatase (PTP-ζ). Hence, IL-34 takes part in a number of biological activities owing to its involvement in different signaling pathways. This review was done to analyze the recent studies on the functions of IL-34 in progression of diseases. The role of IL-34 under the physiological and pathological settings is studied by reviewing current data. In the last ten years, studies suggested that the IL-34 was involved in the regulation of morbid states such as inflammatory diseases, infections, transplant rejection, autoimmune diseases, neurologic diseases, and cancer. In general, the involvement of IL-34 is observed in many serious health ailments like metabolic diseases, heart diseases, infections and even cancer. As such, IL-34 can be regarded as a therapeutic target, potential biomarker or as a therapeutic tool, which ought to be assessed in future research activities.
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Affiliation(s)
- Prerona Boruah
- Shanghai Veterinary Research Institute, Shanghai, China; School of Biotechnology and Bioinformatics, D.Y. Patil Deemed to be University, Navi Mumbai, India
| | - Nikhita Deka
- Department of Life Sciences, Dibrugarh University, Assam, India
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21
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Liu Y, Si ZZ, Zou CJ, Mei X, Li XF, Luo H, Shen Y, Hu J, Li XX, Wu L. Targeting neuroinflammation in Alzheimer’s disease: from mechanisms to clinical applications. Neural Regen Res 2023; 18:708-715. [DOI: 10.4103/1673-5374.353484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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22
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Implications of fractalkine on glial function, ablation and glial proteins/receptors/markers—understanding its therapeutic usefulness in neurological settings: a narrative review. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-022-00446-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Abstract
Background
Fractalkine (CX3CL1) is a chemokine predominantly released by neurons. As a signaling molecule, CX3CL1 facilitates talk between neurons and glia. CX3CL1 is considered as a potential target which could alleviate neuroinflammation. However, certain controversial results and ambiguous role of CX3CL1 make it inexorable to decipher the overall effects of CX3CL1 on the physiopathology of glial cells.
Main body of the abstract
Implications of cross-talk between CX3CL1 and different glial proteins/receptors/markers will give a bird eye view of the therapeutic significance of CX3CL1. Keeping with the need, this review identifies the effects of CX3CL1 on glial physiopathology, glial ablation, and gives a wide coverage on the effects of CX3CL1 on certain glial proteins/receptors/markers.
Short conclusion
Pinpoint prediction of the therapeutic effect of CX3CL1 on neuroinflammation needs further research. This is owing to certain obscure roles and implications of CX3CL1 on different glial proteins/receptors/markers, which are crucial under neurological settings. Further challenges are imposed due to the dichotomous roles played by CX3CL1. The age-old chemokine shows many newer scopes of research in near future. Thus, overall assessment of the effect of CX3CL1 becomes crucial prior to its administration in neuroinflammation.
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23
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Freuchet A, Salama A, Bézie S, Tesson L, Rémy S, Humeau R, Règue H, Sérazin C, Flippe L, Peterson P, Vimond N, Usal C, Ménoret S, Heslan JM, Duteille F, Blanchard F, Giral M, Colonna M, Anegon I, Guillonneau C. IL-34 deficiency impairs FOXP3 + Treg function in a model of autoimmune colitis and decreases immune tolerance homeostasis. Clin Transl Med 2022; 12:e988. [PMID: 36030499 PMCID: PMC9420423 DOI: 10.1002/ctm2.988] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 07/01/2022] [Accepted: 07/07/2022] [Indexed: 12/19/2022] Open
Abstract
Background Immune homeostasis requires fully functional Tregs with a stable phenotype to control autoimmunity. Although IL‐34 is a cytokine first described as mainly involved in monocyte cell survival and differentiation, we recently described its expression by CD8+ Tregs in a rat model of transplantation tolerance and by activated FOXP3+ CD4+ and CD8+ Tregs in human healthy individuals. However, its role in autoimmunity and potential in human diseases remains to be determined. Methods We generated Il34−/− rats and using both Il34−/− rats and mice, we investigated their phenotype under inflammatory conditions. Using Il34−/− rats, we further analyzed the impact of the absence of expression of IL‐34 for CD4+ Tregs suppressive function. We investigated the potential of IL‐34 in human disease to prevent xenogeneic GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, taking advantage of a biocollection, we investigated the correlation between presence of IL‐34 in the serum and kidney transplant rejection. Results Here we report that the absence of expression of IL‐34 in Il34−/− rats and mice leads to an unstable immune phenotype, with production of multiple auto‐antibodies, exacerbated under inflammatory conditions with increased susceptibility to DSS‐ and TNBS‐colitis in Il34−/− animals. Moreover, we revealed the striking inability of Il34−/− CD4+ Tregs to protect Il2rg−/− rats from a wasting disease induced by transfer of pathogenic cells, in contrast to Il34+/+ CD4+ Tregs. We also showed that IL‐34 treatment delayed EAE in mice as well as GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, we show that presence of IL‐34 in the serum is associated with a longer rejection‐free period in kidney transplanted patients. Conclusion Altogether, our data emphasize on the crucial necessity of IL‐34 for immune homeostasis and for CD4+ Tregs suppressive function. Our data also shows the therapeutic potential of IL‐34 in human transplantation and auto‐immunity. Highlights
Absence of expression of IL‐34 in Il34−/− rats and mice leads to an unstable immune phenotype, with a production of multiple auto‐antibodies and exacerbated immune pathology under inflammatory conditions. Il34−/− CD4+ Tregs are unable to protect Il2rg−/− rats from colitis induced by transfer of pathogenic cells. IL‐34 treatment delayed EAE in mice, as well as acute GVHD and human skin allograft rejection in immune‐humanized immunodeficient NSG mice.
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Affiliation(s)
- Antoine Freuchet
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Apolline Salama
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Séverine Bézie
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Laurent Tesson
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Séverine Rémy
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Romain Humeau
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Hadrien Règue
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Céline Sérazin
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Léa Flippe
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Pärt Peterson
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Nadège Vimond
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Claire Usal
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Séverine Ménoret
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France.,CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes Université, Nantes, France
| | - Jean-Marie Heslan
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Franck Duteille
- Chirurgie Plastique Reconstructrice et Esthétique, CHU Nantes, Nantes, France
| | - Frédéric Blanchard
- INSERM UMR1238, Bone Sarcoma and remodeling of calcified tissues, Nantes University, Nantes, France
| | - Magali Giral
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Ignacio Anegon
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
| | - Carole Guillonneau
- Nantes Université, CHU Nantes, CNRS, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN5, Nantes, F-44000, France
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González-Sánchez HM, Baek JH, Weinmann-Menke J, Ajay AK, Charles JFF, Noda M, Franklin RA, Rodríguez-Morales P, Kelley VR. IL-34 and protein-tyrosine phosphatase receptor type-zeta-dependent mechanisms limit arthritis in mice. J Transl Med 2022; 102:846-858. [PMID: 35288653 DOI: 10.1038/s41374-022-00772-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/02/2022] [Accepted: 02/08/2022] [Indexed: 11/09/2022] Open
Abstract
Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis.
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Affiliation(s)
- Hilda Minerva González-Sánchez
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.,CONACyT - Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Mexico
| | - Jea-Hyun Baek
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.,School of Life Science, Handong Global University, Pohang, Gyeongbuk, Republic of Korea
| | - Julia Weinmann-Menke
- Department of Nephrology and Rheumatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Amrendra Kumar Ajay
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | | | - Masaharu Noda
- Homeostatic Mechanism Research Unit, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan
| | - Ruth Anne Franklin
- Department of Immunology, Harvard Medical School, Boston, MA, USA.,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | | | - Vicki Rubin Kelley
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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25
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Thuraisingham RA. A kinetic scheme to examine the role of glial cells in the pathogenesis of Alzheimer's disease. Metab Brain Dis 2022; 37:801-805. [PMID: 35032278 DOI: 10.1007/s11011-022-00902-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 01/03/2022] [Indexed: 11/26/2022]
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disorder that leads to severe impairments in cognitive functions including memory and learning. An improved kinetic model is proposed here to understand the pathogenesis of AD in particular the role of glial cells in the presence of amyloid plaques and neurofibrillary tangles (NFTs). The kinetic model describes the production of activated microglia and astroglia. It involves two rate equations and incorporates the dual role of these glial cells which can function as neuroprotective and as neurotoxic cells. Examination of the steady state solutions of the model predicts an increase in population of these glial cells as (AD) progresses, and that this continues to increase linearly even after the amyloid population has reached a plateau.This is in agreement with experimental data. Limiting AD to the effect of amyloid peptides alone is incorrect and the role of neurofibrillary tangles, clearance rate of dead neurons and neuroinflammation from glial cells are vital and must be included in understanding the pathogenesis of AD. The study shows that increasing the clearance of dead neurons and use of any method to deactivate the glial cells will diminish the progression of AD.
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26
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Guan Y, Zhang L, Wang S, Deng Y, Zhou H, Chen D, Zhang L. The role of microglia in Alzheimer's disease and progress of treatment. IBRAIN 2022; 8:37-47. [PMID: 37786418 PMCID: PMC10529349 DOI: 10.1002/ibra.12023] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 10/04/2023]
Abstract
Microglia are permanent immune cells of the central nervous system. Microglia play an important role in the pathological process of Alzheimer's disease (AD). They are mainly involved in the uptake and clearance of amyloid-β (Aβ), as well as the formation of neuroinflammation. We found that overactivated microglia increase Aβ and Tau, and Aβ and Tau in turn act as activators of microglia. Additionally, various cytokines and proteins, high cholesterol, and telomere shortening are all associated with microglia activation. More activated microglia induce the release of inflammatory and anti-inflammatory factors to regulate inflammation, while microglia express multiple homologous receptors that bind to neuroimmunomodulators to prevent microglia overactivation. Moreover, aging of the body promotes neuroinflammation by increasing the response to IFN-γ (interferon-γ), and aging of the microglia themselves promotes AD by inducing the accumulation of large amounts of iron and reducing autophagy by regulating protein levels. Cognitive dysfunction occurs when activated microglia induce an increase in beta oligomers, promoting the production of pro-inflammatory factors that alter the shape, composition, and density of synapses. Based on their correlation, microglia-mediated AD therapy as well as the corresponding targets and drugs are discussed. In contrast to similar reviews, this article also summarizes some novel microglia-mediated AD treatment methods over the recent years.
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Affiliation(s)
- Yi‐Huan Guan
- Department of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Ling‐Jing Zhang
- Department of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Shi‐Ya Wang
- Department of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Ya‐Dan Deng
- Department of AnesthesiologyZunyi Medical UniversityZunyiGuizhouChina
| | - Hong‐Su Zhou
- Department of AnesthesiaGraduate School of Zunyi Medical UniversityZunyiGuizhouChina
| | - Dong‐Qing Chen
- Department of AnesthesiaGraduate School of Zunyi Medical UniversityZunyiGuizhouChina
| | - Lan‐Chun Zhang
- Department of ZoologyKunming Medical UniversityKunmingChina
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27
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Pons V, Rivest S. Targeting Systemic Innate Immune Cells as a Therapeutic Avenue for Alzheimer Disease. Pharmacol Rev 2022; 74:1-17. [PMID: 34987086 DOI: 10.1124/pharmrev.121.000400] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer disease (AD) is the first progressive neurodegenerative disease worldwide, and the disease is characterized by an accumulation of amyloid in the brain and neurovasculature that triggers cognitive decline and neuroinflammation. The innate immune system has a preponderant role in AD. The last decade, scientists focused their efforts on therapies aiming to modulate innate immunity. The latter is of great interest, since they participate to the inflammation and phagocytose the amyloid in the brain and blood vessels. We and others have developed pharmacological approaches to stimulate these cells using various ligands. These include toll-like receptor 4, macrophage colony stimulating factor, and more recently nucleotide-binding oligomerization domain-containing 2 receptors. This review will discuss the great potential to take advantage of the innate immune system to fight naturally against amyloid β accumulation and prevent its detrimental consequence on brain functions and its vascular system. SIGNIFICANCE STATEMENT: The focus on amyloid β removal from the perivascular space rather than targeting CNS plaque formation and clearance represents a new direction with a great potential. Small molecules able to act at the level of peripheral immunity would constitute a novel approach for tackling aberrant central nervous system biology, one of which we believe would have the potential of generating a lot of interest.
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Affiliation(s)
- Vincent Pons
- Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Québec City, QC G1V 4G2, Canada
| | - Serge Rivest
- Neuroscience Laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier Boul., Québec City, QC G1V 4G2, Canada
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28
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Zhang G, Wang Z, Hu H, Zhao M, Sun L. Microglia in Alzheimer's Disease: A Target for Therapeutic Intervention. Front Cell Neurosci 2021; 15:749587. [PMID: 34899188 PMCID: PMC8651709 DOI: 10.3389/fncel.2021.749587] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/28/2021] [Indexed: 12/31/2022] Open
Abstract
Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.
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Affiliation(s)
- Guimei Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zicheng Wang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Huiling Hu
- Department of Intensive Care Unit, The Affiliated Hospital of Qingdao University, Shandong, China
| | - Meng Zhao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Li Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, China
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29
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Takata K, Ginhoux F, Shimohama S. Roles of microglia in Alzheimer's disease and impact of new findings on microglial heterogeneity as a target for therapeutic intervention. Biochem Pharmacol 2021; 192:114754. [PMID: 34480881 DOI: 10.1016/j.bcp.2021.114754] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/25/2022]
Abstract
Microglia are specialized macrophages that reside within the central nervous system and play key roles in brain immunity, development and homeostasis. Recent studies also revealed functions of microglia in neuroprotection and neuroinflammation, leading to the discovery that microglia are involved in several brain pathologies including Alzheimer's disease (AD). However, the beneficial and detrimental actions of this intriguing cell population can be challenging to dissect: the advent of single-cell and single-nucleus transcriptomic technologies has revolutionized our understanding of the heterogeneity of multiple cell types and is now being applied to the study of microglia in health and disease. Here, we review recent findings on microglial biology, focusing on insights from single cell transcriptomic studies and the heterogeneity that they reveal, and consider the impact of these findings on our understanding of AD. We also discuss how microglia might represent a next-generation therapeutic target for treatment of AD and other neuroinflammatory conditions.
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Affiliation(s)
- Kazuyuki Takata
- Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore; Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Translational Immunology Institute, SingHealth/Duke-NUS, Academic Medical Centre, The Academia, Singapore 169856, Singapore
| | - Shun Shimohama
- Department of Neurology, Sapporo Medical University, School of Medicine, Sapporo 060-8543, Japan
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30
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Niedzwiedz-Massey VM, Douglas JC, Rafferty T, Wight PA, Kane CJM, Drew PD. Ethanol modulation of hippocampal neuroinflammation, myelination, and neurodevelopment in a postnatal mouse model of fetal alcohol spectrum disorders. Neurotoxicol Teratol 2021; 87:107015. [PMID: 34256161 PMCID: PMC8440486 DOI: 10.1016/j.ntt.2021.107015] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/24/2021] [Accepted: 07/08/2021] [Indexed: 01/15/2023]
Abstract
Fetal alcohol spectrum disorders (FASD) are alarmingly common and result in significant personal and societal loss. Neuropathology of the hippocampus is common in FASD leading to aberrant cognitive function. In the current study, we evaluated the effects of ethanol on the expression of a targeted set of molecules involved in neuroinflammation, myelination, neurotransmission, and neuron function in the developing hippocampus in a postnatal model of FASD. Mice were treated with ethanol from P4-P9, hippocampi were isolated 24 h after the final treatment at P10, and mRNA levels were quantitated by qRT-PCR. We evaluated the effects of ethanol on both pro-inflammatory and anti-inflammatory molecules in the hippocampus and identified novel mechanisms by which ethanol induces neuroinflammation. We further demonstrated that ethanol decreased expression of molecules associated with mature oligodendrocytes and greatly diminished expression of a lacZ reporter driven by the first half of the myelin proteolipid protein (PLP) gene (PLP1). In addition, ethanol caused a decrease in genes expressed in oligodendrocyte progenitor cells (OPCs). Together, these studies suggest ethanol may modulate pathogenesis in the developing hippocampus through effects on cells of the oligodendrocyte lineage, resulting in altered oligodendrogenesis and myelination. We also observed differential expression of molecules important in synaptic plasticity, neurogenesis, and neurotransmission. Collectively, the molecules evaluated in these studies may play a role in ethanol-induced pathology in the developing hippocampus and contribute to cognitive impairment associated with FASD. A better understanding of these molecules and their effects on the developing hippocampus may lead to novel treatment strategies for FASD.
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Affiliation(s)
- Victoria M Niedzwiedz-Massey
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - James C Douglas
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Tonya Rafferty
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Patricia A Wight
- Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Cynthia J M Kane
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Paul D Drew
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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31
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Chhetri G. Emerging roles of IL-34 in neurodegenerative and neurological infectious disease. Int J Neurosci 2021; 133:660-671. [PMID: 34347576 DOI: 10.1080/00207454.2021.1963962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Neurological infections are often devastating in their clinical presentation. Although significant advances have made in neuroimaging techniques and molecular tools for diagnosis, as well as in anti-infective therapy, these diseases always difficult to diagnose and treat. Neuroparasitic infections and virus infections lead to neurological infections. In the nervous system, various cytokines and chemokines act as neuroinflammatory agents, neuromodulators, regulate neurodevelopment, and synaptic transmission. Among the most important cytokines, interleukins (ILs) are a large group of immunomodulatory proteins that elicit a wide variety of responses in cells and tissues. These ILs are involved in pro and anti-inflammatory effects, systemic inflammation, immune system modulation and play crucial roles in fighting cancer, infectious disease, and neurological disorders. Interleukin-34 (IL-34) identified by screening a comprehensive human protein library containing ∼3400 secreted and extracellular domain proteins in a human monocyte viability assay. Recent evidence has disclosed the crucial roles of IL-34 in the proliferation and differentiation of mononuclear phagocyte lineage cells, osteoclastogenesis, and inflammation. Additionally, IL-34 plays an important role in development, homeostasis, and disease. Dysregulation in IL-34 function can lead to various inflammatory and infectious diseases (e.g. Inflammatory bowel disease, liver fibrosis, Systemic Lupus erythematosus, rheumatoid arthritis), neurological disorders (e.g. Alzheimer disease) and neurological infectious disease (e.g. West Nile virus disease). In this review, we explore the biological role of IL-34 in addition to various impairments caused by dysregulation in IL-34 and discuss their potential links that may lead to important therapeutic and/or preventive strategies for these disorders.
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Affiliation(s)
- Gaurav Chhetri
- School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai, P.R. China
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32
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Sousa L, Guarda M, Meneses MJ, Macedo MP, Vicente Miranda H. Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases. J Pathol 2021; 255:346-361. [PMID: 34396529 DOI: 10.1002/path.5777] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/01/2021] [Accepted: 08/09/2021] [Indexed: 11/11/2022]
Abstract
Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-β peptide, glucagon, islet amyloid polypeptide (IAPP) and insulin-like growth factors, that have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytical functions such as a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid-β and α-synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Luís Sousa
- CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal
| | - Mariana Guarda
- CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal
| | - Maria João Meneses
- CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal.,APDP-Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal
| | - M Paula Macedo
- CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal.,APDP-Diabetes Portugal Education and Research Center (APDP-ERC), Lisbon, Portugal.,Departamento de Ciências Médicas, Instituto de Biomedicina - iBiMED, Universidade de Aveiro, Aveiro, Portugal
| | - Hugo Vicente Miranda
- CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal
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Neckles VN, Feliciano DM. From seed to flower: blossoming of microglia in development and brain repair. Cell Tissue Res 2021; 387:377-389. [PMID: 34151391 DOI: 10.1007/s00441-021-03486-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/09/2021] [Indexed: 12/23/2022]
Abstract
Physiological functions require coordination of processes between diverse organs, tissues, and cells. This integrative view of science has reemerged complementary to the reductionist philosophy of studying individual cell types. An integrative approach has proven particularly powerful within the field of neuroscience where, intermingled among the most numerous neural cell types of the brain, are immune cells called microglia. Microglia act as a line of defense in the CNS by phagocytizing harmful pathogens and cellular debris and by releasing a variety of factors that mediate immune responses. However, microglia are also appreciated as critical mediators of neurophysiology making them a desired target to rectify neuropathological states. The goal of this review is to discuss microglia ontogenesis, referred to as microgliogenesis, a term that encompasses the events that drive the production, differentiation, migration, and maturation of microglia and opportunities to target microglia for brain repair.
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Affiliation(s)
- Victoria N Neckles
- Department of Biological Sciences, Clemson University, Clemson, SC, 29634-0314, USA
| | - David M Feliciano
- Department of Biological Sciences, Clemson University, Clemson, SC, 29634-0314, USA.
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34
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Hammond BP, Manek R, Kerr BJ, Macauley MS, Plemel JR. Regulation of microglia population dynamics throughout development, health, and disease. Glia 2021; 69:2771-2797. [PMID: 34115410 DOI: 10.1002/glia.24047] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/20/2021] [Accepted: 05/28/2021] [Indexed: 12/11/2022]
Abstract
The dynamic expansions and contractions of the microglia population in the central nervous system (CNS) to achieve homeostasis are likely vital for their function. Microglia respond to injury or disease but also help guide neurodevelopment, modulate neural circuitry throughout life, and direct regeneration. Throughout these processes, microglia density changes, as does the volume of area that each microglia surveys. Given that microglia are responsible for sensing subtle alterations to their environment, a change in their density could affect their capacity to mobilize rapidly. In this review, we attempt to synthesize the current literature on the ligands and conditions that promote microglial proliferation across development, adulthood, and neurodegenerative conditions. Microglia display an impressive proliferative capacity during development and in neurodegenerative diseases that is almost completely absent at homeostasis. However, the appropriate function of microglia in each state is critically dependent on density fluctuations that are primarily induced by proliferation. Proliferation is a natural microglial response to insult and often serves neuroprotective functions. In contrast, inappropriate microglial proliferation, whether too much or too little, often precipitates undesirable consequences for nervous system health. Thus, fluctuations in the microglia population are tightly regulated to ensure these immune cells can execute their diverse functions.
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Affiliation(s)
- Brady P Hammond
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rupali Manek
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Bradley J Kerr
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.,Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Matthew S Macauley
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Jason R Plemel
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.,Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Alberta, Canada
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35
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Vogrinc D, Goričar K, Dolžan V. Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review. Front Aging Neurosci 2021; 13:646901. [PMID: 33815092 PMCID: PMC8012500 DOI: 10.3389/fnagi.2021.646901] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 02/16/2021] [Indexed: 12/14/2022] Open
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.
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Affiliation(s)
| | | | - Vita Dolžan
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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36
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Exposure of Mesenchymal Stem Cells to an Alzheimer's Disease Environment Enhances Therapeutic Effects. Stem Cells Int 2021; 2021:6660186. [PMID: 33815510 PMCID: PMC7988745 DOI: 10.1155/2021/6660186] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/07/2021] [Accepted: 02/19/2021] [Indexed: 01/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of Alzheimer's disease (AD). Previous studies suggested that the coculture of human MSCs with AD in an in vitro model reduced the expression of amyloid-beta 42 (Aβ42) in the medium as well as the overexpression of amyloid-beta- (Aβ-) degrading enzymes such as neprilysin (NEP). We focused on the role of primed MSCs (human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exposed to an AD cell line via a coculture system) in reducing the levels of Aβ and inhibiting cell death. We demonstrated that mouse groups treated with naïve MSCs and primed MSCs showed significant reductions in cell death, ubiquitin conjugate levels, and Aβ levels, but the effects were greater in primed MSCs. Also, mRNA sequencing data analysis indicated that high levels of TGF-β induced primed-MSCs. Furthermore, treatment with TGF-β reduced Aβ expression in an AD transgenic mouse model. These results highlighted AD environmental preconditioning is a promising strategy to reduce cell death and ubiquitin conjugate levels and maintain the stemness of MSCs. Further, these data suggest that human WJ-MSCs exposed to an AD environment may represent a promising and novel therapy for AD.
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37
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Freuchet A, Salama A, Remy S, Guillonneau C, Anegon I. IL-34 and CSF-1, deciphering similarities and differences at steady state and in diseases. J Leukoc Biol 2021; 110:771-796. [PMID: 33600012 DOI: 10.1002/jlb.3ru1120-773r] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/04/2021] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
Although IL-34 and CSF-1 share actions as key mediators of monocytes/macrophages survival and differentiation, they also display differences that should be identified to better define their respective roles in health and diseases. IL-34 displays low sequence homology with CSF-1 but has a similar general structure and they both bind to a common receptor CSF-1R, although binding and subsequent intracellular signaling shows differences. CSF-1R expression has been until now mainly described at a steady state in monocytes/macrophages and myeloid dendritic cells, as well as in some cancers. IL-34 has also 2 other receptors, protein-tyrosine phosphatase zeta (PTPζ) and CD138 (Syndecan-1), expressed in some epithelium, cells of the central nervous system (CNS), as well as in numerous cancers. While most, if not all, of CSF-1 actions are mediated through monocyte/macrophages, IL-34 has also other potential actions through PTPζ and CD138. Additionally, IL-34 and CSF-1 are produced by different cells in different tissues. This review describes and discusses similarities and differences between IL-34 and CSF-1 at steady state and in pathological situations and identifies possible ways to target IL-34, CSF-1, and its receptors.
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Affiliation(s)
- Antoine Freuchet
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Apolline Salama
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Séverine Remy
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Carole Guillonneau
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Ignacio Anegon
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
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38
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Kinoshita M, Oyanagi K, Kondo Y, Ishizawa K, Ishihara K, Yoshida M, Inoue T, Mitsuyama Y, Yoshida K, Yamada M, Sekijima Y, Ikeda SI. Pathologic basis of the preferential thinning of thecorpus callosum in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). eNeurologicalSci 2021; 22:100310. [PMID: 33553700 PMCID: PMC7844436 DOI: 10.1016/j.ensci.2021.100310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/02/2020] [Accepted: 12/31/2020] [Indexed: 01/13/2023] Open
Abstract
Background Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and “focal lesions” of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017). Methods Seven autopsied brains of ALSP and five controls were neuropathologically examined. Results Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the “focal lesions” were identical with those of centrum semiovale. Conclusion Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, “focal lesions” were formed in connection with the lesions in centrum semiovale.
Preferential thinning and “focal lesions” of corpus callosum in ALSP. Seven autopsied brains of ALSP and five controls were neuropathologically examined. Larger spheroids and more microglial alteration in corpus callosum than centrum semiovale. “Focal lesions” were formed in connection with the lesions in the centrum semiovale. Peculiar morphological change of microglia leads to the preferential thinning of corpus callosum.
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Affiliation(s)
- Michiaki Kinoshita
- Department of Neurology, Suwa Red Cross Hospital, 5-11-50 Kogandori, Suwa 392-8510, Japan
| | - Kiyomitsu Oyanagi
- Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Yasufumi Kondo
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Keisuke Ishizawa
- Departments of Neurology and Pathology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
| | - Kenji Ishihara
- Department of Internal Medicine, Ushioda General Hospital, 1-6-20 Yako, Tsurumi-ku, Yokohama 230-0001, Japan
| | - Mari Yoshida
- Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan
| | - Teruhiko Inoue
- Psychogeriatric Center, Daigo Hospital, 1270 Nagata, Mimata-chou, Kitamorokata-gun, Miyazaki 889-1911, Japan
| | - Yoshio Mitsuyama
- Psychogeriatric Center, Daigo Hospital, 1270 Nagata, Mimata-chou, Kitamorokata-gun, Miyazaki 889-1911, Japan
| | - Kunihiro Yoshida
- Division of Neurogenetics, Department of Brain Disease Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Mitsunori Yamada
- Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Yoshiki Sekijima
- Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Shu-Ichi Ikeda
- Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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Pons V, Lévesque P, Plante MM, Rivest S. Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer's disease. Alzheimers Res Ther 2021; 13:8. [PMID: 33402196 PMCID: PMC7783991 DOI: 10.1186/s13195-020-00747-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/09/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. METHODS Here, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice. RESULTS Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain. CONCLUSIONS Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.
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Affiliation(s)
- Vincent Pons
- Neuroscience laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier boulevard, Québec City, QC G1V 4G2 Canada
| | - Pascal Lévesque
- Neuroscience laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier boulevard, Québec City, QC G1V 4G2 Canada
| | - Marie-Michèle Plante
- Neuroscience laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier boulevard, Québec City, QC G1V 4G2 Canada
| | - Serge Rivest
- Neuroscience laboratory, CHU de Québec Research Center and Department of Molecular Medicine, Faculty of Medicine, Laval University, 2705 Laurier boulevard, Québec City, QC G1V 4G2 Canada
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40
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Muñoz-Garcia J, Cochonneau D, Télétchéa S, Moranton E, Lanoe D, Brion R, Lézot F, Heymann MF, Heymann D. The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis. Theranostics 2021; 11:1568-1593. [PMID: 33408768 PMCID: PMC7778581 DOI: 10.7150/thno.50683] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/03/2020] [Indexed: 12/19/2022] Open
Abstract
Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.
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Affiliation(s)
- Javier Muñoz-Garcia
- Université de Nantes, Institut de Cancérologie de l'Ouest, Saint-Herblain, F-44805, France
- SATT Ouest Valorisation, Nantes, France
| | - Denis Cochonneau
- Université de Nantes, Institut de Cancérologie de l'Ouest, Saint-Herblain, F-44805, France
| | | | - Emilie Moranton
- Université de Nantes, Institut de Cancérologie de l'Ouest, Saint-Herblain, F-44805, France
| | - Didier Lanoe
- Université de Nantes, Institut de Cancérologie de l'Ouest, Saint-Herblain, F-44805, France
| | - Régis Brion
- Université de Nantes, INSERM, U1238, Nantes, France
| | | | | | - Dominique Heymann
- Université de Nantes, Institut de Cancérologie de l'Ouest, Saint-Herblain, F-44805, France
- Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK
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41
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Soytürk H, Yılmaz M. A comparison of IL-17 and IL-34 concentrations in the cerebrospinal fluid of patients with acute inflammatory demyelinating neuropathy and chronic inflammatory demyelinating polyneuropathy. ACTA ACUST UNITED AC 2020; 66:1583-1588. [PMID: 33295414 DOI: 10.1590/1806-9282.66.11.1583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 07/02/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The role of interleukins, such as IL-17 and IL-34, in the pathogenesis of autoimmune diseases has been established in the literature. In the current study, we aimed to identify the concentrations of IL-17 (IL-17A, IL-17F) and IL-34 in the cerebrospinal fluid (CSF) of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and acute inflammatory demyelinating neuropathy (AIDN). METHODS We included in this study 8 patients with CIDP (none of them receiving immunomodulatory or immunosuppressant therapy), 7 patients with Guillain-Barre syndrome (GBS, AIDN), and 7 control subjects. The CIDP and AIDN diagnoses were made by clinical evaluation and electrophysiological investigations according to international criteria. CSF samples were obtained appropriately, and the levels of IL-17A, IL-17F, and IL-34 were measured by ELISA kits. RESULTS The concentrations of IL-17A, IL-17F, and IL-34 were higher in those with CIDP and AIDN compared to the controls (p=0.005, p=0.01, and p=0.001, respectively). While IL-34 levels were significantly higher in AIDN patients than in CIDP patients (p=0.04), there were no significant differences between the AIDN and CIDP groups with regard to the levels of IL-17A and IL-17F (p=0.4 and p=0.2, respectively). CONCLUSION Our results indicate that IL-17A, IL-17F, and IL-34 levels may have a role in CIDP and AIDN. Furthermore, the difference in the IL-34 levels of patients with AIDN and CIDP may indicate an important difference between the pathogenesis of these two sets of the disease.
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Affiliation(s)
| | - Murat Yılmaz
- Bolu Abant Izzet Baysal University, Faculty Of Medical School, Department of Neurology Gölköy/Bolu, Turkey
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42
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Saifullah MAB, Komine O, Dong Y, Fukumoto K, Sobue A, Endo F, Saito T, Saido TC, Yamanaka K, Mizoguchi H. Touchscreen-based location discrimination and paired associate learning tasks detect cognitive impairment at an early stage in an App knock-in mouse model of Alzheimer's disease. Mol Brain 2020; 13:147. [PMID: 33183323 PMCID: PMC7664057 DOI: 10.1186/s13041-020-00690-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 10/28/2020] [Indexed: 02/08/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline with accumulation of amyloid beta (Aβ) and neurofibrillary tangles that usually begins 15–30 years before clinical diagnosis. Rodent models that recapitulate aggressive Aβ and/or the pathology of neurofibrillary tangles are essential for AD research. Accordingly, non-invasive early detection systems in these animal models are required to evaluate the phenotypic changes, elucidate the mechanism of disease progression, and facilitate development of novel therapeutic approaches. Although many behavioral tests efficiently reveal cognitive impairments at the later stage of the disease in AD models, it has been challenging to detect such impairments at the early stage. To address this issue, we subjected 4–6-month-old male AppNL−G−F/NL−G−F knock-in (App-KI) mice to touchscreen-based location discrimination (LD), different object–location paired-associate learning (dPAL), and reversal learning tests, and compared the results with those of the classical Morris water maze test. These tests are mainly dependent on the brain regions prone to Aβ accumulation at the earliest stages of the disease. At 4–6 months, considered to represent the early stage of disease when mice exhibit initial deposition of Aβ and slight gliosis, the classical Morris water maze test revealed no difference between groups, whereas touchscreen-based LD and dPAL tasks revealed significant impairments in task performance. Our report is the first to confirm that a systematic touchscreen-based behavioral test battery can sensitively detect the early stage of cognitive decline in an AD-linked App-KI mouse model. This system could be applied in future translational research.
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Affiliation(s)
- Md Ali Bin Saifullah
- Research Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan
| | - Okiru Komine
- Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan
| | - Yutao Dong
- Research Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.,Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8560, Japan
| | - Kazuya Fukumoto
- Research Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan
| | - Akira Sobue
- Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan
| | - Fumito Endo
- Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan
| | - Takashi Saito
- Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan.,Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.,Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Takaomi C Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan
| | - Koji Yamanaka
- Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan
| | - Hiroyuki Mizoguchi
- Research Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan. .,Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8560, Japan.
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43
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Benn CL, Dawson LA. Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease. Front Aging Neurosci 2020; 12:242. [PMID: 33117143 PMCID: PMC7494159 DOI: 10.3389/fnagi.2020.00242] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022] Open
Abstract
Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity.
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44
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Lelios I, Cansever D, Utz SG, Mildenberger W, Stifter SA, Greter M. Emerging roles of IL-34 in health and disease. J Exp Med 2020; 217:133604. [PMID: 31940023 PMCID: PMC7062519 DOI: 10.1084/jem.20190290] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/11/2019] [Accepted: 11/26/2019] [Indexed: 12/14/2022] Open
Abstract
Macrophages are part of the innate immune system and are present in every organ of the body. They fulfill critical roles in tissue homeostasis and development and are involved in various pathologies. An essential factor for the development, homeostasis, and function of mononuclear phagocytes is the colony stimulating factor-1 receptor (CSF-1R), which has two known ligands: CSF-1 and interleukin-34 (IL-34). While CSF-1 has been extensively studied, the biology and functions of IL-34 are only now beginning to be uncovered. In this review, we discuss recent advances of IL-34 biology in health and disease with a specific focus on mononuclear phagocytes.
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Affiliation(s)
- Iva Lelios
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Dilay Cansever
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Sebastian G Utz
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Wiebke Mildenberger
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Sebastian A Stifter
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Melanie Greter
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
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45
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Yu C, Zhang P, Zhang TF, Sun L. IL-34 regulates the inflammatory response and anti-bacterial immune defense of Japanese flounder Paralichthys olivaceus. FISH & SHELLFISH IMMUNOLOGY 2020; 104:228-236. [PMID: 32502613 DOI: 10.1016/j.fsi.2020.05.073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/24/2020] [Accepted: 05/26/2020] [Indexed: 06/11/2023]
Abstract
Interleukin (IL)-34 is a relatively recently discovered cytokine with pleiotropic effects on various cellular activities, including immune response. In fish, the knowledge on the function of IL-34 is limited. In the present work, we investigated the function of Japanese flounder Paralichthys olivaceus IL-34 (PoIL-34) in association with inflammation and immune defense. PoIL-34 possesses the conserved structure of IL-34 superfamily and shares 21.52% sequence identity with murine IL-34. PoIL-34 expression was detected in a wide range of tissues of flounder, in particular intestine, and was regulated to a significant extent by bacterial infection in a time-dependent fashion. In vitro studies showed that recombinant PoIL-34 (rPoIL-34) bound peripheral blood leukocytes (PBLs) and promoted ROS production, acid phosphatase activity, and cellular resistance against bacterial infection. At the molecular level, rPoIL-34 enhanced the expressions of inflammatory cytokines and specific JAK and STAT genes. Similar stimulatory effects of rPoIL-34 were observed in vivo. When PoIL-34 was overexpressed in flounder, the expressions of pro- and anti-inflammatory mediators were significantly affected in a tissue-dependent manner, which correlated with an augmented ability of the fish to eliminate invading pathogens from tissues. Together, these results indicated that PoIL-34 regulated inflammatory response probably via specific JAK/STAT pathways and had a significant influence on the immune defense of flounder against bacterial infection.
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Affiliation(s)
- Chao Yu
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Peng Zhang
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Teng-Fei Zhang
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Li Sun
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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46
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Ennerfelt HE, Lukens JR. The role of innate immunity in Alzheimer's disease. Immunol Rev 2020; 297:225-246. [PMID: 32588460 PMCID: PMC7783860 DOI: 10.1111/imr.12896] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/23/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022]
Abstract
The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain-resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.
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Affiliation(s)
- Hannah E. Ennerfelt
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
- Cell and Molecular Biology Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - John R. Lukens
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
- Cell and Molecular Biology Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
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47
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Gow DJ, Jackson H, Forsythe P, Nuttall T, Gow AG, Mellanby RJ, Hume DA. Measurement of serum Interleukin 34 (IL‐34) and correlation with severity and pruritus scores in client‐owned dogs with atopic dermatitis. Vet Dermatol 2020; 31:359-e94. [PMID: 32794277 DOI: 10.1111/vde.12873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Deborah J. Gow
- R(D)SVS and The Roslin Institute Hospital for Small Animals The University of Edinburgh Edinburgh EH25 9RG Scotland, UK
| | - Hilary Jackson
- The Dermatology Referral Service 528 Paisley Road West Glasgow G51 1RN UK
| | - Peter Forsythe
- The Dermatology Referral Service 528 Paisley Road West Glasgow G51 1RN UK
| | - Tim Nuttall
- R(D)SVS and The Roslin Institute Hospital for Small Animals The University of Edinburgh Edinburgh EH25 9RG Scotland, UK
| | - Adam G. Gow
- R(D)SVS and The Roslin Institute Hospital for Small Animals The University of Edinburgh Edinburgh EH25 9RG Scotland, UK
| | - Richard J. Mellanby
- R(D)SVS and The Roslin Institute Hospital for Small Animals The University of Edinburgh Edinburgh EH25 9RG Scotland, UK
| | - David A. Hume
- R(D)SVS and The Roslin Institute Hospital for Small Animals The University of Edinburgh Edinburgh EH25 9RG Scotland, UK
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48
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Zuroff LR, Torbati T, Hart NJ, Fuchs DT, Sheyn J, Rentsendorj A, Koronyo Y, Hayden EY, Teplow DB, Black KL, Koronyo-Hamaoui M. Effects of IL-34 on Macrophage Immunological Profile in Response to Alzheimer's-Related Aβ 42 Assemblies. Front Immunol 2020; 11:1449. [PMID: 32765504 PMCID: PMC7378440 DOI: 10.3389/fimmu.2020.01449] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022] Open
Abstract
Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that peripheral BM-derived monocyte/macrophages (BMMO) play a key role in the physiological clearance of cerebral amyloid β-protein (Aβ). Aβ42 forms are especially neurotoxic and highly associated with Alzheimer's disease (AD). As a ligand of CSF1R, IL-34 may be relevant to innate immune responses in AD. To investigate how IL-34 affects macrophage phenotype in response to structurally defined and stabilized Aβ42 oligomers and preformed fibrils, we characterized murine BMMO cultured in media containing M-CSF, IL-34, or regimens involving both cytokines. We found that the immunological profile and activation phenotype of IL-34-stimulated BMMO differed significantly from those cultured with M-CSF alone. Specifically, macrophage uptake of fibrillar or oligomeric Aβ42 was markedly reduced following exposure to IL-34 compared to M-CSF. Surface expression of type B scavenger receptor CD36, known to facilitate Aβ recognition and uptake, was modified following treatment with IL-34. Similarly, IL-34 macrophages expressed lower levels of proteins involved in both Aβ uptake (triggering receptor expressed on myeloid cells 2, TREM2) as well as Aβ-degradation (matrix metallopeptidase 9, MMP-9). Interestingly, intracellular compartmentalization of Aβ visualized by staining of early endosome antigen 1 (EEA1) was not affected by IL-34. Macrophage characteristics associated with an anti-inflammatory and pro-wound healing phenotype, including processes length and morphology, were also quantified, and macrophages stimulated with IL-34 alone displayed less process elongation in response to Aβ42 compared to those cultured with M-CSF. Further, monocytes treated with IL-34 alone yielded fewer mature macrophages than those treated with M-CSF alone or in combination with IL-34. Our data indicate that IL-34 impairs monocyte differentiation into macrophages and reduces their ability to uptake pathological forms of Aβ. Given the critical role of macrophage-mediated Aβ clearance in both murine models and patients with AD, future work should investigate the therapeutic potential of modulating IL-34 in vivo to increase macrophage-mediated Aβ clearance and prevent disease development.
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Affiliation(s)
- Leah R Zuroff
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Tania Torbati
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States.,Western University of Health Sciences College of Osteopathic Medicine of the Pacific, Pomona, CA, United States
| | - Nadav J Hart
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Dieu-Trang Fuchs
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Julia Sheyn
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Altan Rentsendorj
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yosef Koronyo
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Eric Y Hayden
- Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - David B Teplow
- Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
| | - Keith L Black
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Maya Koronyo-Hamaoui
- Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Biomedical Sciences, Applied Cellular Biology and Physiology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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49
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Neganova ME, Aleksandrova YR, Nebogatikov VO, Klochkov SG, Ustyugov AA. Promising Molecular Targets for Pharmacological Therapy of Neurodegenerative Pathologies. Acta Naturae 2020; 12:60-80. [PMID: 33173597 PMCID: PMC7604899 DOI: 10.32607/actanaturae.10925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022] Open
Abstract
Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, α-synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.
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Affiliation(s)
- M. E. Neganova
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - Yu. R. Aleksandrova
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - V. O. Nebogatikov
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - S. G. Klochkov
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
| | - A. A. Ustyugov
- Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Moscow region, Chernogolovka, 142432 Russia
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50
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Martin-Estebane M, Gomez-Nicola D. Targeting Microglial Population Dynamics in Alzheimer's Disease: Are We Ready for a Potential Impact on Immune Function? Front Cell Neurosci 2020; 14:149. [PMID: 32581720 PMCID: PMC7289918 DOI: 10.3389/fncel.2020.00149] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 05/05/2020] [Indexed: 12/15/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, affecting two-thirds of people with dementia in the world. To date, no disease-modifying treatments are available to stop or delay the progression of AD. This chronic neurodegenerative disease is dominated by a strong innate immune response, whereby microglia plays a central role as the main resident macrophage of the brain. Recent genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) located in microglial genes and associated with a delayed onset of AD, highlighting the important role of these cells on the onset and/or progression of the disease. These findings have increased the interest in targeting microglia-associated neuroinflammation as a potentially disease-modifying therapeutic approach for AD. In this review we provide an overview on the contribution of microglia to the pathophysiology of AD, focusing on the main regulatory pathways controlling microglial population dynamics during the neuroinflammatory response, such as the colony-stimulating factor 1 receptor (CSF1R), its ligands (the colony-stimulating factor 1 and interleukin 34) and the transcription factor PU.1. We also discuss the current therapeutic strategies targeting proliferation to modulate microglia-associated neuroinflammation and their potential impact on peripheral immune cell populations in the short and long-term. Understanding the effects of immunomodulatory approaches on microglia and other immune cell types might be critical for developing specific, effective, and safe therapies for neurodegenerative diseases.
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Affiliation(s)
- Maria Martin-Estebane
- School of Biological Sciences, University of Southampton, Southampton, United Kingdom
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton, United Kingdom
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