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Jahan I, Harun-Ur-Rashid M, Islam MA, Sharmin F, Al Jaouni SK, Kaki AM, Selim S. Neuronal plasticity and its role in Alzheimer's disease and Parkinson's disease. Neural Regen Res 2026; 21:107-125. [PMID: 39688547 PMCID: PMC12094540 DOI: 10.4103/nrr.nrr-d-24-01019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/09/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Neuronal plasticity, the brain's ability to adapt structurally and functionally, is essential for learning, memory, and recovery from injuries. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, this plasticity is disrupted, leading to cognitive and motor deficits. This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease. Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function, while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control. Enhancing neuronal plasticity offers therapeutic potential for these diseases. A systematic literature review was conducted using databases such as PubMed, Scopus, and Google Scholar, focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease. Data synthesis identified key themes such as synaptic mechanisms, neurogenesis, and therapeutic strategies, linking molecular insights to clinical applications. Results highlight that targeting synaptic plasticity mechanisms, such as long-term potentiation and long-term depression, shows promise. Neurotrophic factors, advanced imaging techniques, and molecular tools (e.g., clustered regularly interspaced short palindromic repeats and optogenetics) are crucial in understanding and enhancing plasticity. Current therapies, including dopamine replacement, deep brain stimulation, and lifestyle interventions, demonstrate the potential to alleviate symptoms and improve outcomes. In conclusion, enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases. Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Israt Jahan
- Genetic Engineering and Biotechnology Research Laboratory (GEBRL), Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka, Bangladesh
| | - Mohammad Harun-Ur-Rashid
- Department of Chemistry, International University of Business Agriculture and Technology (IUBAT), Sector 10, Uttara Model Town, Dhaka, Bangladesh
| | - Md. Aminul Islam
- Genetic Engineering and Biotechnology Research Laboratory (GEBRL), Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka, Bangladesh
| | - Farhana Sharmin
- Department of Anatomy, Shaheed Suhrawardy Medical College, Dhaka, Bangladesh
| | - Soad K. Al Jaouni
- Department of Hematology/Oncology, Yousef Abdulatif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdullah M. Kaki
- Department of Anesthesia and Pain Medicine, Director of Pain Clinic, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Samy Selim
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia
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Hroudová J, Fišar Z. Alzheimer's disease approaches - Focusing on pathology, biomarkers and clinical trial candidates. Prog Neuropsychopharmacol Biol Psychiatry 2024; 134:111069. [PMID: 38917881 DOI: 10.1016/j.pnpbp.2024.111069] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/19/2024] [Accepted: 06/19/2024] [Indexed: 06/27/2024]
Abstract
The strategy for the development of new drugs for Alzheimer's disease (AD) recognizes that an effective therapy requires early therapeutic intervention and a multifactorial approach that considers the individual initiators of AD development. Current knowledge of AD includes the understanding of pathophysiology, risk factors, biomarkers, and the evolving patterns of biomarker abnormalities. This knowledge is essential in identifying potential molecular targets for new drug development. This review summarizes promising AD drug candidates, many of which are currently in phase 2 or 3 clinical trials. New agents are classified according to the Common Alzheimer's Disease Research Ontology (CADRO). The main targets of new drugs for AD are processes related to amyloid beta and tau neurotoxicity, neurotransmission, inflammation, metabolism and bioenergetics, synaptic plasticity, and oxidative stress. These interventions are aimed at preventing disease onset and slowing or eliminating disease progression. The efficacy of pharmacotherapy may be enhanced by combining these drugs with other treatments, antioxidants, and dietary supplements. Ongoing research into AD pathophysiology, risk factors, biomarkers, and the dynamics of biomarker abnormalities may contribute to the understanding of AD and offer hope for effective therapeutic strategies in the near future.
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Affiliation(s)
- Jana Hroudová
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic.
| | - Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague 2, Czech Republic
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3
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Naveed K, Rashidi-Ranjbar N, Kumar S, Zomorrodi R, Blumberger DM, Fischer CE, Sanches M, Mulsant BH, Pollock BG, Voineskos AN, Rajji TK. Effect of dorsolateral prefrontal cortex structural measures on neuroplasticity and response to paired-associative stimulation in Alzheimer's dementia. Philos Trans R Soc Lond B Biol Sci 2024; 379:20230233. [PMID: 38853564 PMCID: PMC11343312 DOI: 10.1098/rstb.2023.0233] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 12/04/2023] [Accepted: 01/15/2024] [Indexed: 06/11/2024] Open
Abstract
Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Affiliation(s)
- K. Naveed
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - N. Rashidi-Ranjbar
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, 209 Victoria Street, Toronto, OntarioM5B 1T8, Canada
| | - S. Kumar
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - R. Zomorrodi
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
| | - D. M. Blumberger
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - C. E. Fischer
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, 209 Victoria Street, Toronto, OntarioM5B 1T8, Canada
| | - M. Sanches
- Biostatistics Core, Centre for Addiction and Mental Health, 60 White Squirrel Way, Toronto, OntarioM6J 1H4, Canada
| | - B. H. Mulsant
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - B. G. Pollock
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - A. N. Voineskos
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
| | - T. K. Rajji
- Temerty Faculty of Medicine, University of Toronto, 1 King’s College Cir, Toronto, OntarioM5S 1A8, Canada
- Toronto Dementia Research Alliance, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
- Campbell Family Mental Health Research Institute, CAMH, 479 Spadina Avenue, Toronto, OntarioM5S 2S1, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 250 College Street, Toronto, OntarioM5T 1R8, Canada
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Oriá RB, Smith CJ, Ashford JW, Vitek MP, Guerrant RL. Pros and Cons of APOE4 Homozygosity and Effects on Neuroplasticity, Malnutrition, and Infections in Early Life Adversity, Alzheimer's Disease, and Alzheimer's Prevention. J Alzheimers Dis 2024; 100:S179-S185. [PMID: 39093076 DOI: 10.3233/jad-240888] [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: 08/04/2024]
Abstract
Fortea et al.'s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer's disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.
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Affiliation(s)
- Reinaldo B Oriá
- Department of Morphology, Laboratory of Tissue Healing, Ontogeny, and Nutrition, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza, Brazil
| | - Carr J Smith
- Society for Brain Mapping and Therapeutics, Pacific Palisades, CA, USA
| | - J Wesson Ashford
- War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA
| | - Michael P Vitek
- Department of Neurology, Duke University Medical Center, Durham, NC, USA
| | - Richard L Guerrant
- Department of Medicine, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, VA, USA
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Amato LG, Vergani AA, Lassi M, Fabbiani C, Mazzeo S, Burali R, Nacmias B, Sorbi S, Mannella R, Grippo A, Bessi V, Mazzoni A. Personalized modeling of Alzheimer's disease progression estimates neurodegeneration severity from EEG recordings. ALZHEIMER'S & DEMENTIA (AMSTERDAM, NETHERLANDS) 2024; 16:e12526. [PMID: 38371358 PMCID: PMC10870085 DOI: 10.1002/dad2.12526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/13/2023] [Accepted: 12/19/2023] [Indexed: 02/20/2024]
Abstract
INTRODUCTION Early identification of Alzheimer's disease (AD) is necessary for a timely onset of therapeutic care. However, cortical structural alterations associated with AD are difficult to discern. METHODS We developed a cortical model of AD-related neurodegeneration accounting for slowing of local dynamics and global connectivity degradation. In a monocentric study we collected electroencephalography (EEG) recordings at rest from participants in healthy (HC, n = 17), subjective cognitive decline (SCD, n = 58), and mild cognitive impairment (MCI, n = 44) conditions. For each patient, we estimated neurodegeneration model parameters based on individual EEG recordings. RESULTS Our model outperformed standard EEG analysis not only in discriminating between HC and MCI conditions (F1 score 0.95 vs 0.75) but also in identifying SCD patients with biological hallmarks of AD in the cerebrospinal fluid (recall 0.87 vs 0.50). DISCUSSION Personalized models could (1) support classification of MCI, (2) assess the presence of AD pathology, and (3) estimate the risk of cognitive decline progression, based only on economical and non-invasive EEG recordings. Highlights Personalized cortical model estimating structural alterations from EEG recordings.Discrimination of Mild Cognitive Impairment (MCI) and Healthy (HC) subjects (95%)Prediction of biological markers of Alzheimer's in Subjective Decline (SCD) Subjects (87%)Transition correctly predicted for 3/3 subjects that converted from SCD to MCI after 1y.
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Affiliation(s)
- Lorenzo Gaetano Amato
- The BioRobotics InstituteSant'Anna School of Advanced StudiesPisaItaly
- Department of Excellence in Robotics and AISant'Anna School of Advanced StudiesPisaItaly
| | - Alberto Arturo Vergani
- The BioRobotics InstituteSant'Anna School of Advanced StudiesPisaItaly
- Department of Excellence in Robotics and AISant'Anna School of Advanced StudiesPisaItaly
| | - Michael Lassi
- The BioRobotics InstituteSant'Anna School of Advanced StudiesPisaItaly
- Department of Excellence in Robotics and AISant'Anna School of Advanced StudiesPisaItaly
| | - Carlo Fabbiani
- IRCSS Fondazione Don Carlo GnocchiFlorenceItaly
- Department of NeurosciencePsychology, Drug Research and Child HealthCareggi University HospitalFlorenceItaly
| | - Salvatore Mazzeo
- IRCSS Fondazione Don Carlo GnocchiFlorenceItaly
- Department of NeurosciencePsychology, Drug Research and Child HealthCareggi University HospitalFlorenceItaly
| | | | - Benedetta Nacmias
- IRCSS Fondazione Don Carlo GnocchiFlorenceItaly
- Department of NeurosciencePsychology, Drug Research and Child HealthCareggi University HospitalFlorenceItaly
| | - Sandro Sorbi
- IRCSS Fondazione Don Carlo GnocchiFlorenceItaly
- Department of NeurosciencePsychology, Drug Research and Child HealthCareggi University HospitalFlorenceItaly
| | | | | | - Valentina Bessi
- Department of NeurosciencePsychology, Drug Research and Child HealthCareggi University HospitalFlorenceItaly
| | - Alberto Mazzoni
- The BioRobotics InstituteSant'Anna School of Advanced StudiesPisaItaly
- Department of Excellence in Robotics and AISant'Anna School of Advanced StudiesPisaItaly
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Winkelman MJ, Szabo A, Frecska E. The potential of psychedelics for the treatment of Alzheimer's disease and related dementias. Eur Neuropsychopharmacol 2023; 76:3-16. [PMID: 37451163 DOI: 10.1016/j.euroneuro.2023.07.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically relevant natural products and their synthetic analogues. This paper reviews evidence for effectiveness of natural and synthetic psychedelics in the treatment of AD causes and symptoms. The plastogenic effects of serotonergic psychedelics illustrate that they have efficacy for addressing multiple facets of AD pathology. We review findings illustrating neuroplasticity mechanisms of classic (serotonergic) and non-classic psychedelics that indicate their potential as treatments for AD and related dementias. Classic psychedelics modulate glutamatergic neurotransmission and stimulate synaptic and network remodeling that facilitates synaptic, structural and behavioral plasticity. Up-regulation of neurotrophic factors enable psychedelics to promote neuronal survival and glutamate-driven neuroplasticity. Muscimol modulation of GABAAR reduces Aβ-induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in Aβ toxicity. Classic psychedelics also activate mTOR intracellular effector pathways in brain regions that show atrophy in AD. The potential of psychedelics to treat AD involves their ability to induce structural and functional neural plasticity in brain circuits and slow or reverse brain atrophy. Psychedelics stimulate neurotrophic pathways, increase neurogenesis and produce long-lasting neural changes through rewiring pathological neurocircuitry. Psychedelic effects on 5-HT receptor target genes and induction of synaptic, structural, and functional changes in neurons and networks enable them to promote and enhance brain functional connectivity and address diverse mechanisms underlying degenerative neurological disorders. These findings provide a rationale for immediate investigation of psychedelics as treatments for AD patients.
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Affiliation(s)
- Michael James Winkelman
- School of Human Evolution and Social Change, Arizona State University, Tempe, AZ, United States
| | - Attila Szabo
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway.
| | - Ede Frecska
- Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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7
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Uras I, Karayel-Basar M, Sahin B, Baykal AT. Detection of early proteomic alterations in 5xFAD Alzheimer's disease neonatal mouse model via MALDI-MSI. Alzheimers Dement 2023; 19:4572-4589. [PMID: 36934297 DOI: 10.1002/alz.13008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 03/20/2023]
Abstract
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder, characterized by memory deficit and dementia. AD is considered a multifactorial disorder where multiple processes like amyloid-beta and tau accumulation, axonal degeneration, synaptic plasticity, and autophagic processes plays an important role. In this study, the spatial proteomic differences in the neonatal 5xFAD brain tissue were investigated using MALDI-MSI coupled to LC-MS/MS, and the statistically significantly altered proteins were associated with AD. Thirty-five differentially expressed proteins (DEPs) between the brain tissues of neonatal 5xFAD and their littermate mice were detected via MALDI-MSI technique. Among the 35 proteins identified, 26 of them were directly associated with AD. Our results indicated a remarkable resemblance in the protein expression profiles of neonatal 5xFAD brain when compared to AD patient specimens or AD mouse models. These findings showed that the molecular alterations in the AD brain existed even at birth and that some proteins are neurodegenerative presages in neonatal AD brain. HIGHLIGHTS: Spatial proteomic alterations in the 5xFAD mouse brain compared to the littermate. 26 out of 35 differentially expressed proteins associated with Alzheimer's disease (AD). Molecular alterations and neurodegenerative presages in neonatal AD brain. Alterations in the synaptic function an early and common neurobiological thread.
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Affiliation(s)
- Irep Uras
- Department of Biochemistry and Molecular Biology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Merve Karayel-Basar
- Department of Biochemistry and Molecular Biology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Betul Sahin
- Acibadem Labmed Clinical Laboratories, Istanbul, Turkey
| | - Ahmet Tarik Baykal
- Department of Medical Biochemistry, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
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8
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Ashford JW. Neuroplasticity: The Critical Issue for Alzheimer's Disease and Links to Obesity and Depression. Am J Geriatr Psychiatry 2023; 31:867-875. [PMID: 37481402 DOI: 10.1016/j.jagp.2023.07.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/24/2023]
Affiliation(s)
- J Wesson Ashford
- Department of Psychiatry & Behavioral Sciences, VA Palo Alto Health Care System, Stanford University, Palo Alto, CA.
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9
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Timalsina B, Haque MN, Dash R, Choi HJ, Ghimire N, Moon IS. Neuronal Differentiation and Outgrowth Effect of Thymol in Trachyspermum ammi Seed Extract via BDNF/TrkB Signaling Pathway in Prenatal Maternal Supplementation and Primary Hippocampal Culture. Int J Mol Sci 2023; 24:ijms24108565. [PMID: 37239909 DOI: 10.3390/ijms24108565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/06/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Reviving the neuronal functions in neurodegenerative disorders requires the promotion of neurite outgrowth. Thymol, which is a principal component of Trachyspermum ammi seed extract (TASE), is reported to have neuroprotective effects. However, the effects of thymol and TASE on neuronal differentiation and outgrowth are yet to be studied. This study is the first report investigating the neuronal growth and maturation effects of TASE and thymol. Pregnant mice were orally supplemented with TASE (250 and 500 mg/kg), thymol (50 and 100 mg/kg), vehicle, and positive controls. The supplementation significantly upregulated the expression of brain-derived neurotrophic factor (BDNF) and early neuritogenesis markers in the pups' brains at post-natal day 1 (P1). Similarly, the BDNF level was significantly upregulated in the P12 pups' brains. Furthermore, TASE (75 and 100 µg/mL) and thymol (10 and 20 µM) enhanced the neuronal polarity, early neurite arborization, and maturation of hippocampal neurons in a dose-dependent manner in primary hippocampal cultures. The stimulatory activities of TASE and thymol on neurite extension involved TrkB signaling, as evidenced by attenuation via ANA-12 (5 µM), which is a specific TrkB inhibitor. Moreover, TASE and thymol rescued the nocodazole-induced blunted neurite extension in primary hippocampal cultures, suggesting their role as a potent microtubule stabilizing agent. These findings demonstrate the potent capacities of TASE and thymol in promoting neuronal development and reconstruction of neuronal circuitry, which are often compromised in neurodegenerative diseases and acute brain injuries.
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Affiliation(s)
- Binod Timalsina
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Md Nazmul Haque
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
- Department of Fisheries Biology and Genetics, Patuakhali Science and Technology University, Patuakhali 8602, Bangladesh
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Ho Jin Choi
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
| | - Nisha Ghimire
- Department of Life Science and Biochemical Engineering, Graduate School, Sun Moon University, Asan 31460, Republic of Korea
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
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10
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Babić Leko M, Langer Horvat L, Španić Popovački E, Zubčić K, Hof PR, Šimić G. Metals in Alzheimer's Disease. Biomedicines 2023; 11:1161. [PMID: 37189779 PMCID: PMC10136077 DOI: 10.3390/biomedicines11041161] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
The role of metals in the pathogenesis of Alzheimer's disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies that (1) compared the metal concentrations between AD patients and healthy controls, (2) correlated concentrations of AD cerebrospinal fluid (CSF) biomarkers with metal concentrations, and (3) used Mendelian randomization (MR) to assess the potential metal contributions to AD risk. Although many studies have examined various metals in dementia patients, understanding the dynamics of metals in these patients remains difficult due to considerable inconsistencies among the results of individual studies. The most consistent findings were for Zn and Cu, with most studies observing a decrease in Zn levels and an increase in Cu levels in AD patients. However, several studies found no such relation. Because few studies have compared metal levels with biomarker levels in the CSF of AD patients, more research of this type is required. Given that MR is revolutionizing epidemiologic research, additional MR studies that include participants from diverse ethnic backgrounds to assess the causal relationship between metals and AD risk are critical.
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Affiliation(s)
- Mirjana Babić Leko
- Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
| | - Lea Langer Horvat
- Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
| | - Ena Španić Popovački
- Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
| | - Klara Zubčić
- Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
| | - Patrick R. Hof
- Nash Family Department of Neuroscience, Friedman Brain Institute and Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Goran Šimić
- Department of Neuroscience, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
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Lu CH, Chang HT, Hsu LF, Lee MH, Cheng J, Wu DC, Lin WY. In Silico and In Vitro Screening of Serine Racemase Agonist and In Vivo Efficacy on Alzheimer's Disease Drosophila melanogaster. Pharmaceuticals (Basel) 2023; 16:280. [PMID: 37259423 PMCID: PMC9962741 DOI: 10.3390/ph16020280] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 06/07/2025] Open
Abstract
The NMDA receptor hypofunction has been implicated in schizophrenia, memory impairment, and Alzheimer's disease. Modulating the abundance of D-serine, a co-agonist of the NMDA receptor, is a strategy to treat symptoms of the NMDA receptor hypofunction. In contrast to D-amino acid oxidase (DAAO) inhibitors, which aim at decreasing the loss of D-serine, this study tried to identify serine racemase (SRR) agonists, which boost the conversion of L-serine to D-serine. We used holo and apo structures of human SRR for the molecular docking against the National Cancer Institute (NCI) and ZINC compound databases and validated their efficacy by in vitro SRR activity assay. We identified NSC294149 (2-amino-3-(3-nitroimidazo[1,2-a]pyridin-2-yl)sulfanylpropanoic acid) as a potential SRR agonist and confirmed its amelioration of the hazard ratio of survival of the AD model of fruit fly (Drosophila melanogaster). These results suggest that the SRR agonist could be a drug design target against the NMDA receptor hypofunction symptoms.
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Affiliation(s)
- Chih-Hao Lu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan
| | - Hao-Teng Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
| | - Lee-Fen Hsu
- Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi City 613, Chiayi County, Taiwan
- Chronic Disease and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi City 613, Chiayi County, Taiwan
- Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Puzi City 613, Chiayi County, Taiwan
| | - Ming-Hsueh Lee
- Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Puzi City 613, Chiayi County, Taiwan
| | - Jack Cheng
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan
| | - Dong Chuan Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- Translational Medicine Research Center, China Medical University Hospital, Taichung 40402, Taiwan
| | - Wei-Yong Lin
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan
- Brain Diseases Research Center, China Medical University, Taichung 40402, Taiwan
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12
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Rao RV, Subramaniam KG, Gregory J, Bredesen AL, Coward C, Okada S, Kelly L, Bredesen DE. Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer's Disease and MCI: A Review. Int J Mol Sci 2023; 24:ijms24021659. [PMID: 36675177 PMCID: PMC9865291 DOI: 10.3390/ijms24021659] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/03/2023] [Accepted: 01/09/2023] [Indexed: 01/18/2023] Open
Abstract
Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disease typically characterized by memory loss, personality changes, and a decline in overall cognitive function. Usually manifesting in individuals over the age of 60, this is the most prevalent type of dementia and remains the fifth leading cause of death among Americans aged 65 and older. While the development of effective treatment and prevention for AD is a major healthcare goal, unfortunately, therapeutic approaches to date have yet to find a treatment plan that produces long-term cognitive improvement. Drugs that may be able to slow down the progression rate of AD are being introduced to the market; however, there has been no previous solution for preventing or reversing the disease-associated cognitive decline. Recent studies have identified several factors that contribute to the progression and severity of the disease: diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins. Thus, increasing evidence supports dietary and other lifestyle changes as potentially effective ways to prevent, slow, or reverse AD progression. Studies also have demonstrated that a personalized, multi-therapeutic approach is needed to improve metabolic abnormalities and AD-associated cognitive decline. These studies suggest the effects of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, in the AD process. Therefore a personalized, multi-therapeutic program based on an individual's genetics and biochemistry may be preferable over a single-drug/mono-therapeutic approach. This article reviews these multi-therapeutic strategies that identify and attenuate all the risk factors specific to each affected individual. This article systematically reviews studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline. We included high-quality clinical trials and observational studies that focused on the cognitive effects of programs comprising lifestyle, physical, and mental activity, as well as nutritional aspects. Articles from PubMed Central, Scopus, and Google Scholar databases were collected, and abstracts were reviewed for relevance to the subject matter. Epidemiological, pathological, toxicological, genetic, and biochemical studies have all concluded that AD represents a complex network insufficiency. The research studies explored in this manuscript confirm the need for a multifactorial approach to target the various risk factors of AD. A single-drug approach may delay the progression of memory loss but, to date, has not prevented or reversed it. Diet, physical activity, sleep, stress, and environment all contribute to the progression of the disease, and, therefore, a multi-factorial optimization of network support and function offers a rational therapeutic strategy. Thus, a multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may be more effective than a mono-therapeutic approach.
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Affiliation(s)
- Rammohan V. Rao
- Apollo Health, Burlingame, CA 94011, USA
- Correspondence: (R.V.R.); (D.E.B.)
| | | | | | | | | | - Sho Okada
- Apollo Health, Burlingame, CA 94011, USA
| | | | - Dale E. Bredesen
- Apollo Health, Burlingame, CA 94011, USA
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90024, USA
- Correspondence: (R.V.R.); (D.E.B.)
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13
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Fišar Z. Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets. Biomolecules 2022; 12:1676. [PMID: 36421690 PMCID: PMC9687482 DOI: 10.3390/biom12111676] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/23/2022] [Accepted: 11/09/2022] [Indexed: 08/27/2023] Open
Abstract
Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.
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Affiliation(s)
- Zdeněk Fišar
- Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 11, 120 00 Prague, Czech Republic
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14
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Peng S, Roth AR, Perry BL. A latent variable approach to measuring bridging social capital and examining its association to older adults' cognitive health. Soc Neurosci 2021; 16:684-694. [PMID: 34727017 DOI: 10.1080/17470919.2021.2001368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Access to cognitive stimulation through social interactions is a key mechanism used to explain the association between personal networks, cognitive health, and brain structure in older adults. However, little research has assessed how best to operationalize access to novel or diverse social stimuli using social network measures, many of which were designed to study information diffusion within large whole networks (e.g., structural holes and bridging social capital). Using data from 277 adults in the Social Networks and Alzheimer Disease (SNAD) study, we aimed to evaluate such measures for use in research on cognitive aging using personal social networks. We found a positive association between individual measures of structural holes and cognitive health, but not with brain structure. Further, we extracted a latent measure of bridging social capital using multiple individual measures (i.e., structural holes, network diversity, weak ties, and network size) and found it was significantly associated with cognitive health and brain structure, supporting the utility of this concept and related measures in the study of cognitive aging. Finally, individual measures may underestimate the effects of multidimensional bridging social capital on cognitive health and brain structure compared to a latent measure that combines them.
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Affiliation(s)
- Siyun Peng
- Department of Sociology, Indiana University, Bloomington, IN, USA
| | - Adam R Roth
- Department of Sociology & Network Science Institute, Indiana University
| | - Brea L Perry
- Department of Sociology & Network Science Institute, Indiana University
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15
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Chauveau L, Kuhn E, Palix C, Felisatti F, Ourry V, de La Sayette V, Chételat G, de Flores R. Medial Temporal Lobe Subregional Atrophy in Aging and Alzheimer's Disease: A Longitudinal Study. Front Aging Neurosci 2021; 13:750154. [PMID: 34720998 PMCID: PMC8554299 DOI: 10.3389/fnagi.2021.750154] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/13/2021] [Indexed: 11/13/2022] Open
Abstract
Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.
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Affiliation(s)
- Léa Chauveau
- U1237 PhIND, Inserm, Caen-Normandie University, GIP Cyceron, Caen, France
| | - Elizabeth Kuhn
- U1237 PhIND, Inserm, Caen-Normandie University, GIP Cyceron, Caen, France
| | - Cassandre Palix
- U1237 PhIND, Inserm, Caen-Normandie University, GIP Cyceron, Caen, France
| | | | - Valentin Ourry
- U1237 PhIND, Inserm, Caen-Normandie University, GIP Cyceron, Caen, France.,U1077 NIMH, Inserm, Caen-Normandie University, École Pratique des Hautes Études, Caen, France
| | - Vincent de La Sayette
- U1077 NIMH, Inserm, Caen-Normandie University, École Pratique des Hautes Études, Caen, France
| | - Gaël Chételat
- U1237 PhIND, Inserm, Caen-Normandie University, GIP Cyceron, Caen, France
| | - Robin de Flores
- U1237 PhIND, Inserm, Caen-Normandie University, GIP Cyceron, Caen, France
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16
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Hannan MA, Haque MN, Munni YA, Oktaviani DF, Timalsina B, Dash R, Afrin T, Moon IS. Centella asiatica promotes early differentiation, axodendritic maturation and synaptic formation in primary hippocampal neurons. Neurochem Int 2021; 144:104957. [PMID: 33444677 DOI: 10.1016/j.neuint.2021.104957] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 12/21/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Centella asiatica is a 'medhya-rasayana (nootrophic or memory booster)' herb that has been indicated in Ayurveda for improving memory function and treating dementia disorders. Although the neuroprotective effects of C. asiatica have been reported in earlier studies, the information on whether this nootropic herb could promote early differentiation and development of axon and dendrites in primary hippocampal neurons is currently limited. THE AIM OF THE STUDY To investigate the effects of C. asiatica and asiatic acid, one of the principal active constituents of C. asiatica, on the various stages of neuronal polarity, including early neuronal differentiation, axonal outgrowth, dendritic arborization, axonal maturation, and synaptic formation. MATERIALS AND METHODS Embryonic rat hippocampal neurons were incubated with C. asiatica leaf extract (CAE) or asiatic acid. After an indicated time, neurons were fixed and immunolabeled to visualize the neuronal morphology. Morphometric analyses for early neuronal differentiation, axonal and dendritic maturation and synaptogenesis were performed using Image J software. Neuronal viability was determined using trypan blue exclusion assay. RESULTS CAE at varying concentrations ranging from 3.75 to 15 μg/mL enhanced neurite outgrowth with the highest optimal concentration of 7.5 μg/mL. The effects of CAE commenced immediately after cell seeding, as indicated by its accelerating effect on neuronal differentiation. Subsequently, CAE significantly elaborated dendritic and axonal morphology and facilitated synapse formation. Asiatic acid also facilitated neurite outgrowth, but to a lesser extent than CAE. CONCLUSION These findings revealed that CAE exerted its modulatory effects in every stage of neuronal development, supporting its previously claimed neurotrophic function and suggest that this natural nootropic and its active component asiatic acid can be further investigated to explore a promising solution for degenerative brain disorders and injuries.
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Affiliation(s)
- Md Abdul Hannan
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea; Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Md Nazmul Haque
- Department of Fisheries Biology and Genetics, Patuakhali Science and Technology University, Patuakhali, 8602, Bangladesh
| | - Yeasmin Akter Munni
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Diyah Fatimah Oktaviani
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Binod Timalsina
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Tania Afrin
- Interdisciplinary Institute for Food Security, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea.
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17
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Gurel B, Cansev M, Koc C, Ocalan B, Cakir A, Aydin S, Kahveci N, Ulus IH, Sahin B, Basar MK, Baykal AT. Proteomics Analysis of CA1 Region of the Hippocampus in Pre-, Progression and Pathological Stages in a Mouse Model of the Alzheimer's Disease. Curr Alzheimer Res 2020; 16:613-621. [PMID: 31362689 DOI: 10.2174/1567205016666190730155926] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 03/15/2019] [Accepted: 07/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND CA1 subregion of the hippocampal formation is one of the primarily affected structures in AD, yet not much is known about proteome alterations in the extracellular milieu of this region. OBJECTIVE In this study, we aimed to identify the protein expression alterations throughout the pre-pathological, progression and pathological stages of AD mouse model. METHODS The CA1 region perfusates were collected by in-vivo intracerebral push-pull perfusion from transgenic 5XFAD mice and their non-transgenic littermates at 3, 6 and 12 wereβmonths of age. Morris water maze test and immunohistochemistry staining of A performed to determine the stages of the disease in this mouse model. The protein expression differences were analyzed by label-free shotgun proteomics analysis. RESULTS A total of 251, 213 and 238 proteins were identified in samples obtained from CA1 regions of mice at 3, 6 and 12 months of age, respectively. Of these, 68, 41 and 33 proteins showed statistical significance. Pathway analysis based on the unique and common proteins within the groups revealed that several pathways are dysregulated during different stages of AD. The alterations in glucose and lipid metabolisms respectively in pre-pathologic and progression stages of the disease, lead to imbalances in ROS production via diminished SOD level and impairment of neuronal integrity. CONCLUSION We conclude that CA1 region-specific proteomic analysis of hippocampal degeneration may be useful in identifying the earliest as well as progressional changes that are associated with Alzheimer's disease.
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Affiliation(s)
- Busra Gurel
- Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.,Department of Medical Biochemistry, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Mehmet Cansev
- Department of Pharmacology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Cansu Koc
- Department of Pharmacology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Busra Ocalan
- Department of Physiology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Aysen Cakir
- Department of Physiology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Sami Aydin
- Department of Pharmacology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Nevzat Kahveci
- Department of Physiology, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Ismail Hakki Ulus
- Department of Pharmacology, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Betul Sahin
- Acibadem Labmed R&D Laboratory, Istanbul, Turkey
| | - Merve Karayel Basar
- Department of Medical Biochemistry, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Ahmet Tarik Baykal
- Department of Medical Biochemistry, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
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18
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3β, 6β-dichloro-5-hydroxy-5α-cholestane facilitates neuronal development through modulating TrkA signaling regulated proteins in primary hippocampal neuron. Sci Rep 2019; 9:18919. [PMID: 31831796 PMCID: PMC6908615 DOI: 10.1038/s41598-019-55364-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/27/2019] [Indexed: 12/11/2022] Open
Abstract
Potentiating neuritogenesis through pharmacological intervention might hold therapeutic promise in neurodegenerative disorders and acute brain injury. Here, we investigated the novel neuritogenic potentials of a steroidal chlorohydrin, 3β, 6β-dichloro-5-hydroxy-5α-cholestane (hereafter, SCH) and the change in cellular proteome to gain insight into the underlying mechanism of its neurotrophic activity in hippocampal neurons. Morphometric analysis showed that SCH promoted early neuronal differentiation, dendritic arborization and axonal maturation. Proteomic and bioinformatic analysis revealed that SCH induced upregulation of several proteins, including those associated with neuronal differentiation and development. Immunocytochemical data further indicates that SCH-treated neurons showed upregulation of Hnrnpa2b1 and Map1b, validating their proteomic profiles. In addition, a protein-protein interaction network analysis identified TrkA as a potential target connecting most of the upregulated proteins. The neurite outgrowth effect of SCH was suppressed by TrkA inhibitor, GW441756, verifying TrkA-dependent activity of SCH, which further supports the connection of TrkA with the upregulated proteins. Also, the computational analysis revealed that SCH interacts with the NGF-binding domain of TrkA through Phe327 and Asn355. Collectively, our findings provide evidence that SCH promotes neuronal development via upregulating TrkA-signaling proteins and suggest that SCH could be a promising therapeutic agent in the prevention and treatment of neurodegenerative disorders.
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19
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Korthauer LE, Awe E, Frahmand M, Driscoll I. Genetic Risk for Age-Related Cognitive Impairment Does Not Predict Cognitive Performance in Middle Age. J Alzheimers Dis 2019; 64:459-471. [PMID: 29865048 DOI: 10.3233/jad-171043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Alzheimer's disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40-60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers.
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Affiliation(s)
- Laura E Korthauer
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Elizabeth Awe
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.,Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Marijam Frahmand
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Ira Driscoll
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
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20
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Structural and biological evaluation of a platinum complex as a potential anti-neurodegenerative agent. Inorganica Chim Acta 2019. [DOI: 10.1016/j.ica.2019.03.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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21
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Gołaszewska A, Bik W, Motyl T, Orzechowski A. Bridging the Gap between Alzheimer's Disease and Alzheimer's-like Diseases in Animals. Int J Mol Sci 2019; 20:ijms20071664. [PMID: 30987146 PMCID: PMC6479525 DOI: 10.3390/ijms20071664] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 03/24/2019] [Accepted: 03/31/2019] [Indexed: 12/13/2022] Open
Abstract
The average life span steadily grows in humans and in animals kept as pets or left in sanctuaries making the issue of elderly-associated cognitive impairment a hot-spot for scientists. Alzheimer’s disease (AD) is the most prevalent cause of progressive mental deterioration in aging humans, and there is a growing body of evidence that similar disorders (Alzheimer’s-like diseases, ALD) are observed in animals, more than ever found in senescent individuals. This review reveals up to date knowledge in pathogenesis, hallmarks, diagnostic approaches and modalities in AD faced up with ALD related to different animal species. If found at necropsy, there are striking similarities between senile plaques (SP) and neurofibrillary tangles (NFT) in human and animal brains. Also, the set of clinical symptoms in ALD resembles that observed in AD. At molecular and microscopic levels, the human and animal brain histopathology in AD and ALD shows a great resemblance. AD is fatal, and the etiology is still unknown, although the myriad of efforts and techniques were employed in order to decipher the molecular mechanisms of disease onset and its progression. Nowadays, according to an increasing number of cases reported in animals, apparently, biochemistry of AD and ALD has a lot in common. Described observations point to the importance of extensive in vivo models and extensive pre-clinical studies on aging animals as a suitable model for AD disease.
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Affiliation(s)
- Anita Gołaszewska
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
- Department of Neuroendocrinology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland.
| | - Wojciech Bik
- Department of Neuroendocrinology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland.
| | - Tomasz Motyl
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
| | - Arkadiusz Orzechowski
- Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
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22
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Marston KJ, Brown BM, Rainey-Smith SR, Peiffer JJ. Resistance Exercise-Induced Responses in Physiological Factors Linked with Cognitive Health. J Alzheimers Dis 2019; 68:39-64. [DOI: 10.3233/jad-181079] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Kieran J. Marston
- Department of Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Perth, Western Australia, Australia
- Ageing, Cognition and Exercise (ACE) Research Group, Murdoch University, Perth, Western Australia, Australia
| | - Belinda M. Brown
- Department of Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Perth, Western Australia, Australia
- Ageing, Cognition and Exercise (ACE) Research Group, Murdoch University, Perth, Western Australia, Australia
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
- Australian Alzheimer’s Research Foundation, Sarich Neuroscience Research Institute, Nedlands, Western Australia, Australia
| | - Stephanie R. Rainey-Smith
- Ageing, Cognition and Exercise (ACE) Research Group, Murdoch University, Perth, Western Australia, Australia
- Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
- Australian Alzheimer’s Research Foundation, Sarich Neuroscience Research Institute, Nedlands, Western Australia, Australia
| | - Jeremiah J. Peiffer
- Department of Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Perth, Western Australia, Australia
- Ageing, Cognition and Exercise (ACE) Research Group, Murdoch University, Perth, Western Australia, Australia
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Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer's disease amyloidosis. PLoS One 2019; 14:e0209228. [PMID: 30645585 PMCID: PMC6333398 DOI: 10.1371/journal.pone.0209228] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/30/2018] [Indexed: 01/01/2023] Open
Abstract
Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer’s Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis.
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Haque MN, Mohibbullah M, Hong YK, Moon IS. Calotropis gigantea Promotes Neuritogenesis and Synaptogenesis through Activation of NGF-TrkA-Erk1/2 Signaling in Rat Hippocampal Neurons. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 46:1861-1877. [DOI: 10.1142/s0192415x18500933] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Calotropis gigantea (L.) R. Br (Apocynaceae) (commonly known as milkweed or crown flower) is a large shrub native to temperate regions of Asia, including China, Bangladesh and India and has a long history of use in traditional medicines. In this study, we investigated the neuromodulatory effects of the ethanol extracts of C. gigantea leaves (CGE) during synaptogenesis in the late stage of neuronal development and during early stage neuritogenesis in cultured rat hippocampal neurons. Maximum neuritogenic activity was achieved at a CGE concentration of 7.5[Formula: see text][Formula: see text]g/ml. At this concentration, CGE facilitated the early development of cytoarchitecture, as evidenced by increases in morphometric parameters, such as, the numbers, lengths, and number of branches of initial neurites, axon and dendrites. During the synaptogenic stage (DIV 14), immunocytochemistry (ICC) showed that CGE upregulated synaptic vesicle 2 (SV2, a marker of axon terminals) and postsynaptic density-95 (PSD-95, a postsynaptic marker) and their colocalization. CGE upregulated nerve growth factor (NGF) and activated extracellular signal-regulated kinase 1/2 (Erk1/2), which is blocked by a TrkA-specific inhibitor suggesting the neuritogenic and synaptogenic potential of CGE was due to the activation of NGF-TrkA-Erk1/2 signaling. Moreover, UPLC of CGE did not detect stigmasterol, an active component of C. gigantea. However, the chloroform-methanol and ethyl acetate subfractions of CGE exhibited initial neuritogenic activity, suggesting that multiple active components were responsible for the neurotrophic-mimetic properties of CGE. Our data prove the neuromodulatory ability of CGE and provide a means of identifying new active phytochemicals with potential nootropic, preventative or therapeutic effects on the human brain.
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Affiliation(s)
- Md Nazmul Haque
- Department of Anatomy, Dongguk University Graduate School of Medicine, Gyeongju 38066, Republic of Korea
| | - Md Mohibbullah
- Department of Biotechnology, Pukyong National University, Namku, Busan 48513, Republic of Korea
- Department of Fisheries and Marine Bioscience, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj-8100, Bangladesh
| | - Yong-Ki Hong
- Department of Biotechnology, Pukyong National University, Namku, Busan 48513, Republic of Korea
| | - Il Soo Moon
- Department of Anatomy, Dongguk University Graduate School of Medicine, Gyeongju 38066, Republic of Korea
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Dario MFR, Sara T, Estela CO, Margarita PM, Guillermo ET, Fernando RDF, Javier SL, Carmen P. Stress, Depression, Resilience and Ageing: A Role for the LPA-LPA1 Pathway. Curr Neuropharmacol 2018; 16:271-283. [PMID: 28699486 PMCID: PMC5843979 DOI: 10.2174/1570159x15666170710200352] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 05/26/2017] [Accepted: 06/30/2017] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Chronic stress affects health and the quality of life, with its effects being particularly relevant in ageing due to the psychobiological characteristics of this population. However, while some people develop psychiatric disorders, especially depression, others seem very capable of dealing with adversity. There is no doubt that along with the identification of neurobiological mechanisms involved in developing depression, discovering which factors are involved in positive adaptation under circumstances of extreme difficulty will be crucial for promoting resilience. METHODS Here, we review recent work in our laboratory, using an animal model lacking the LPA1 receptor, together with pharmacological studies and clinical evidence for the possible participation of the LPA1 receptor in mood and resilience to stress. RESULTS Substantial evidence has shown that the LPA1 receptor is involved in emotional regulation and in coping responses to chronic stress, which, if dysfunctional, may induce vulnerability to stress and predisposition to the development of depression. Given that there is commonality of mechanisms between those involved in negative consequences of stress and in ageing, this is not surprising, considering that the LPA1 receptor may be involved in coping with adversity during ageing. CONCLUSION Alterations in this receptor may be a susceptibility factor for the presence of depression and cognitive deficits in the elderly population. However, because this is only a promising hypothesis based on previous data, future studies should focus on the involvement of the LPA-LPA1 pathway in coping with stress and resilience in ageing.
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Affiliation(s)
- Moreno-Fernández Román Dario
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| | - Tabbai Sara
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| | - Castilla-Ortega Estela
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga; Málaga 29010, Spain
| | - Pérez-Martín Margarita
- Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de
Málaga; Málaga 29071, Spain
| | - Estivill-Torrús Guillermo
- Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitarios de Málaga, Málaga, Spain
| | - Rodríguez de Fonseca Fernando
- Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga; Málaga 29010, Spain
| | - Santin Luis Javier
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
| | - Pedraza Carmen
- Departamento de Psicobiología y Metodología de las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga; Málaga 29071, Spain
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Moulin S, Leys D. Stroke occurring in patients with cognitive impairment or dementia. ARQUIVOS DE NEURO-PSIQUIATRIA 2017; 75:117-121. [PMID: 28226082 DOI: 10.1590/0004-282x20160187] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 10/10/2016] [Indexed: 11/22/2022]
Abstract
Objective To determine how pre-stroke cognitive impairment can be detected, its mechanism, and influence on outcome and management. Methods Literature search. Results (i) A systematic approach with the Informant Questionnaire of Cognitive Decline in the Elderly is recommended; (ii) Pre-stroke cognitive impairment may be due to brain lesions of vascular, degenerative, or mixed origin; (iii) Patients with pre-stroke dementia, have worse outcomes, more seizures, delirium, and depression, and higher mortality rates; they often need to be institutionalised after their stroke; (iv) Although the safety profile of treatment is not as good as that of cognitively normal patients, the risk:benefit ratio is in favour of treating these patients like others. Conclusion Patients with cognitive impairment who develop a stroke have worse outcomes, but should be treated like others.
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Affiliation(s)
- Solène Moulin
- Université de Lille. INSERM U 1171, Troubles cognitifs dégénératifs et vasculaires. CHU de Lille, Service de Neurologie, Lille, France
| | - Didier Leys
- Université de Lille. INSERM U 1171, Troubles cognitifs dégénératifs et vasculaires. CHU de Lille, Service de Neurologie, Lille, France
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Mohibbullah M, Bhuiyan MMH, Hannan MA, Getachew P, Hong YK, Choi JS, Choi IS, Moon IS. The Edible Red Alga Porphyra yezoensis Promotes Neuronal Survival and Cytoarchitecture in Primary Hippocampal Neurons. Cell Mol Neurobiol 2016; 36:669-82. [PMID: 26259718 PMCID: PMC11482408 DOI: 10.1007/s10571-015-0247-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 07/28/2015] [Indexed: 12/13/2022]
Abstract
The edible red alga Porphyra yezoensis is among the most popular marine algae and is of economic and medicinal importance. In the present study, the neurotrophic and neuroprotective activities of the ethanol extract of P. yezoensis (PYE) were investigated in primary cultures of hippocampal neurons. Results revealed that PYE significantly increased neurite outgrowth at an optimal concentration of 15 µg/mL. PYE dose-dependently increased viable cells, significantly accelerated the rate of neuronal differentiation in cultures, promoted axodendritic arborization, and eventually induced synaptogenesis. In addition to morphological development, PYE also promoted functional maturation as indicated by the staining of live cultures with FM 1-43. Moreover, PYE increased neuronal survivability, which was attributed to reduced apoptosis and its ROS scavenging activity. Taurine, a major organic acid in PYE (2.584/100 mg of dry PYE) promoted neurite outgrowth in a dose-dependent manner, and this promotion was suppressed by the taurine antagonist isethionic acid. The study indicates that PYE and its active component, taurine, facilitate neuronal development and maturation and have a neuroprotective effect.
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Affiliation(s)
- Md Mohibbullah
- Department of Biotechnology, Pukyong National University, Namku, Busan, 608-737, Republic of Korea
| | | | - Md Abdul Hannan
- Department of Biotechnology, Pukyong National University, Namku, Busan, 608-737, Republic of Korea
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Paulos Getachew
- Department of Biotechnology, Pukyong National University, Namku, Busan, 608-737, Republic of Korea
| | - Yong-Ki Hong
- Department of Biotechnology, Pukyong National University, Namku, Busan, 608-737, Republic of Korea
| | - Jae-Suk Choi
- RIS Center, IACF, Silla University, Sasang-gu, Busan, 617-736, Republic of Korea
| | - In Soon Choi
- RIS Center, IACF, Silla University, Sasang-gu, Busan, 617-736, Republic of Korea
- Department of Biological Science, Silla University, Sasang-gu, Busan, 617-736, Republic of Korea
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 780-714, Republic of Korea.
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Ashford JW. Treatment of Alzheimer's Disease: The Legacy of the Cholinergic Hypothesis, Neuroplasticity, and Future Directions. J Alzheimers Dis 2016; 47:149-56. [PMID: 26402763 DOI: 10.3233/jad-150381] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In this issue, an article by Waring et al. provides a meta-analysis of the effects of apo-lipo-protein E (APOE) genotype on the beneficial effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD). There was no significant effect found. As of 2015, AChEI medications are the mainstay of AD treatment, and APOE genotype is the most significant factor associated with AD causation. This lack of a significant effect of APOE is analyzed with respect to the "Cholinergic Hypothesis" of AD, dating from 1976, through the recognition that cholinergic neurons are not the sole target of AD, but rather that AD attacks all levels of neuroplasticity in the brain, an idea originated by Ashford and Jarvik in 1985 and which still provides the clearest explanation for AD dementia. The "Amyloid Hypothesis" is dissected back to the alpha/beta pathway switching mechanism affecting the nexin-amyloid pre-protein (NAPP switch). The NAPP switch may be the critical neuroplasticity component of all learning involving synapse remodeling and subserve all learning mechanisms. The gamma-secretase cleavage is discussed, and its normal complementary products, beta-amyloid and the NAPP intracellular domain (NAICD), appear to be involved in natural synapse removal, but the link to AD dementia may involve the NAICD rather than beta-amyloid. Understanding neuroplasticity and the critical pathways to AD dementia are needed to determine therapies and preventive strategies for AD. In particular, the effect of APOE on AD predisposition needs to be established and a means found to adjust its effect to prevent AD.
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Justin Cook C, Fletcher JM. Understanding heterogeneity in the effects of birth weight on adult cognition and wages. JOURNAL OF HEALTH ECONOMICS 2015; 41:107-16. [PMID: 25770970 PMCID: PMC4417462 DOI: 10.1016/j.jhealeco.2015.01.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 10/09/2014] [Accepted: 01/14/2015] [Indexed: 05/14/2023]
Abstract
A large economics literature has shown long term impacts of birth weight on adult outcomes, including IQ and earnings that are often robust to sibling or twin fixed effects. We examine potential mechanisms underlying these effects by incorporating findings from the genetics and neuroscience literatures. We use a sample of siblings combined with an "orchids and dandelions hypothesis", where the IQ of genetic dandelions is not affected by in utero nutrition variation but genetic orchids thrive under advantageous conditions and wilt in poor conditions. Indeed, using variation in three candidate genes related to neuroplasticity (APOE, BDNF, and COMT), we find substantial heterogeneity in the associations between birth weight and adult outcomes, where part of the population (i.e., "dandelions") is not affected by birth weight variation. Our results help uncover why birth weight affects adult outcomes.
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Parra MA, Saarimäki H, Bastin ME, Londoño AC, Pettit L, Lopera F, Della Sala S, Abrahams S. Memory binding and white matter integrity in familial Alzheimer's disease. Brain 2015; 138:1355-69. [PMID: 25762465 DOI: 10.1093/brain/awv048] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 12/30/2014] [Indexed: 11/13/2022] Open
Abstract
Binding information in short-term and long-term memory are functions sensitive to Alzheimer's disease. They have been found to be affected in patients who meet criteria for familial Alzheimer's disease due to the mutation E280A of the PSEN1 gene. However, only short-term memory binding has been found to be affected in asymptomatic carriers of this mutation. The neural correlates of this dissociation are poorly understood. The present study used diffusion tensor magnetic resonance imaging to investigate whether the integrity of white matter structures could offer an account. A sample of 19 patients with familial Alzheimer's disease, 18 asymptomatic carriers and 21 non-carrier controls underwent diffusion tensor magnetic resonance imaging, neuropsychological and memory binding assessment. The short-term memory binding task required participants to detect changes across two consecutive screens displaying arrays of shapes, colours, or shape-colour bindings. The long-term memory binding task was a Paired Associates Learning Test. Performance on these tasks were entered into regression models. Relative to controls, patients with familial Alzheimer's disease performed poorly on both memory binding tasks. Asymptomatic carriers differed from controls only in the short-term memory binding task. White matter integrity explained poor memory binding performance only in patients with familial Alzheimer's disease. White matter water diffusion metrics from the frontal lobe accounted for poor performance on both memory binding tasks. Dissociations were found in the genu of corpus callosum which accounted for short-term memory binding impairments and in the hippocampal part of cingulum bundle which accounted for long-term memory binding deficits. The results indicate that white matter structures in the frontal and temporal lobes are vulnerable to the early stages of familial Alzheimer's disease and their damage is associated with impairments in two memory binding functions known to be markers for Alzheimer's disease.
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Affiliation(s)
- Mario A Parra
- 1 Human Cognitive Neuroscience, Psychology, University of Edinburgh, Edinburgh, UK 2 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK 3 UDP-INECO Foundation Core on Neuroscience (UIFCoN), Diego Portales University, Santiago, Chile 4 Alzheimer Scotland Dementia Research Centre and Scottish Dementia Clinical Research Network, NHS Scotland 5 Neuroscience Group, University of Antioquia, Antioquia, Colombia
| | - Heini Saarimäki
- 1 Human Cognitive Neuroscience, Psychology, University of Edinburgh, Edinburgh, UK
| | - Mark E Bastin
- 2 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Ana C Londoño
- 5 Neuroscience Group, University of Antioquia, Antioquia, Colombia
| | - Lewis Pettit
- 1 Human Cognitive Neuroscience, Psychology, University of Edinburgh, Edinburgh, UK
| | - Francisco Lopera
- 5 Neuroscience Group, University of Antioquia, Antioquia, Colombia
| | - Sergio Della Sala
- 1 Human Cognitive Neuroscience, Psychology, University of Edinburgh, Edinburgh, UK 2 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Sharon Abrahams
- 1 Human Cognitive Neuroscience, Psychology, University of Edinburgh, Edinburgh, UK 2 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK 6 Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK
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Haršány M, Tsivgoulis G, Alexandrov AV. Intravenous thrombolysis in acute ischemic stroke: standard and potential future applications. Expert Rev Neurother 2014; 14:879-92. [PMID: 24984941 DOI: 10.1586/14737175.2014.934676] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Acute ischemic stroke is a medical emergency requiring urgent treatment. Randomized clinical trial and Phase IV data have provided unequivocal evidence that intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) improves early functional outcomes by restoring brain perfusion. Moreover, these studies have shed substantial light on the factors which are associated with more favorable outcome with tPA and are related to the highest benefit-to-risk ratio. Stroke physicians should consider vascular imaging techniques to aid decision making with thrombolytic therapy. The presence of intracranial occlusion is the target of treatment with early recanalization being the goal. Successful use of intravenous thrombolysis depends on a sound understanding of the decision-making process and organization of the treating team who strives for early treatment initiation and strict adherence to the protocol. Intravenous rt-PA within 4.5 h of onset should now be a standard treatment of acute disabling ischemic stroke throughout the world. This review also summarizes intravenous thrombolysis contraindications as well as the safety of novel reperfusion therapies including tenecteplase, sonothrombolysis and the combination of alteplase with direct thrombin inhibitors or glycoprotein IIb/IIIa receptor antagonists.
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Affiliation(s)
- Michal Haršány
- International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
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Murao K, Bombois S, Cordonnier C, Hénon H, Bordet R, Pasquier F, Leys D. Influence of cognitive impairment on the management of ischaemic stroke. Rev Neurol (Paris) 2014; 170:177-86. [PMID: 24613474 DOI: 10.1016/j.neurol.2014.01.665] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 01/03/2014] [Accepted: 01/30/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Because of ageing of the population, it is more and more frequent to treat ischaemic stroke patients with pre-stroke cognitive impairment (PSCI). Currently, there is no specific recommendation on ischaemic stroke management in these patients, both at the acute stage and in secondary prevention. However, these patients are less likely to receive treatments proven effective in randomised controlled trials, even in the absence of contra-indication. OBJECTIVE To review the literature to assess efficacy and safety of validated therapies for acute ischaemic stroke and secondary prevention in PSCI patients. RESULTS Most randomised trials did not take into account the pre-stroke cognitive status. The few observational studies conducted at the acute stage or in secondary prevention, did not provide any information that the benefit could be either lost or replaced by harm in the presence of PSCI. CONCLUSIONS There is no reason not to treat ischaemic stroke patients with PSCI according to the currently available recommendations for acute management and secondary prevention. Further observational studies are needed and pre-stroke cognition should be taken into account in future stroke trials.
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Affiliation(s)
- K Murao
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France
| | - S Bombois
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France; Departments of Neurology, Memory Centre, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France.
| | - C Cordonnier
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France; Departments of Neurology, Stroke centre, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France
| | - H Hénon
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France; Departments of Neurology, Stroke centre, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France
| | - R Bordet
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France; Department, of Pharmacology. Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France
| | - F Pasquier
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France; Departments of Neurology, Memory Centre, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France
| | - D Leys
- EA 1046, Departments of Neurology, University Lille North of France, UDSL, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France; Departments of Neurology, Stroke centre, Lille University Hospital, 1, place de Verdun, 59045 Lille cedex, France
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Hannan MA, Kang JY, Mohibbullah M, Hong YK, Lee H, Choi JS, Choi IS, Moon IS. Moringa oleifera with promising neuronal survival and neurite outgrowth promoting potentials. JOURNAL OF ETHNOPHARMACOLOGY 2014; 152:142-150. [PMID: 24389557 DOI: 10.1016/j.jep.2013.12.036] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 12/03/2013] [Accepted: 12/21/2013] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Moringa oleifera Lam. (Moringaceae) by virtue of its high nutritional as well as ethnomedical values has been gaining profound interest both in nutrition and medicinal research. The leaf of this plant is used in ayurvedic medicine to treat paralysis, nervous debility and other nerve disorders. In addition, research evidence also suggests the nootropic as well as neuroprotective roles of Moringa oleifera leaf in animal models. The aim of the present study was to evaluate the effect of Moringa oleifera leaf in the primary hippocampal neurons regarding its neurotrophic and neuroprotective properties. MATERIALS AND METHODS The primary culture of embryonic hippocampal neurons was incubated with the ethanol extract of Moringa oleifera leaf (MOE). After an indicated time, cultures were either stained directly with a lipophilic dye, DiO, or fixed and immunolabeled to visualize the neuronal morphology. Morphometric analyses for neurite maturation and synaptogenesis were performed using Image J software. Neuronal viability was evaluated using trypan blue exclusion and lactate dehydrogenase assays. RESULTS MOE promoted neurite outgrowth in a concentration-dependent manner with an optimal concentration of 30 μg/mL. As a very initial effect, MOE significantly promoted the earlier stages of neuronal differentiation. Subsequently, MOE significantly increased the number and length of dendrites, the length of axon, and the number and length of both dendrite and axonal branches, and eventually facilitated synaptogenesis. The β-carotene, one major compound of MOE, promoted neuritogensis, but the increase was not comparable with the effect of MOE. In addition, MOE supported neuronal survival by protecting neurons from naturally occurring cell death in vitro. CONCLUSIONS Our findings indicate that MOE promotes axodendritic maturation as well as provides neuroprotection suggesting a promising pharmacological importance of this nutritionally and ethnomedically important plant for the well-being of nervous system.
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Affiliation(s)
- Md Abdul Hannan
- Department of Biotechnology, Pukyong National University, Namku, Busan 608-737, Republic of Korea; Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Ji-Young Kang
- Department of Biotechnology, Pukyong National University, Namku, Busan 608-737, Republic of Korea
| | - Md Mohibbullah
- Department of Biotechnology, Pukyong National University, Namku, Busan 608-737, Republic of Korea
| | - Yong-Ki Hong
- Department of Biotechnology, Pukyong National University, Namku, Busan 608-737, Republic of Korea
| | - Hyunsook Lee
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 780-714, Republic of Korea
| | - Jae-Suk Choi
- RIS Center, IACF, Silla University, Sasang-gu, Busan 617-736, Republic of Korea
| | - In Soon Choi
- RIS Center, IACF, Silla University, Sasang-gu, Busan 617-736, Republic of Korea; Department of Biological Science, Silla University, Sasang-gu, Busan 617-736, Republic of Korea
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju 780-714, Republic of Korea.
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Hannan MA, Mohibbullah M, Hwang SY, Lee K, Kim YC, Hong YK, Moon IS. Differential neuritogenic activities of two edible brown macroalgae, Undaria pinnatifida and Saccharina japonica. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2014; 42:1371-84. [PMID: 25413631 DOI: 10.1142/s0192415x14500864] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Undaria pinnatifida (Harvey) Suringar and Saccharina japonica Areschoug are two common seaweeds, and both are known to have numerous pharmacological properties that include neuroprotective effects. In a previous study, we found that the ethanol extracts of U. pinnatifida (UPE) and S. japonica (SJE) had neurite promoting activities on developing hippocampal neurons. In the present study, we studied and compared the effects of UPE and SJE on neuronal maturation. Both UPE and SJE promoted neurite outgrowth in a dose-dependent manner with optimal concentrations of 5 and 15 μg/mL, respectively. Initial neuronal differentiation was significantly promoted by UPE and SJE. Subsequently, treatment with both increased indices of axonal and dendritic cytoarchitecture, such as, the numbers and lengths of primary processes, although only UPE had a significant effect on branching frequencies. In addition, UPE and SJE showed no evidence of cytotoxicity, rather they protected neurons from naturally occurring death in vitro. These results indicate that UPE and SJE promote axodendritic maturation and neuronal survival and suggest that these algal extracts, especially UPE, have beneficial effects on the nervous system.
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Affiliation(s)
- Md Abdul Hannan
- Department of Biotechnology, Pukyong National University, Namku, Busan 608-737, Republic of Korea , Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
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35
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Cheng X, Wu J, Geng M, Xiong J. Role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease. Neurobiol Aging 2013; 35:1217-32. [PMID: 24368087 DOI: 10.1016/j.neurobiolaging.2013.11.021] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Revised: 11/03/2013] [Accepted: 11/24/2013] [Indexed: 01/27/2023]
Abstract
Alzheimer's disease (AD) is the most common form of dementia. Accumulation of amyloid-beta (Aβ) peptides is regarded as the critical component associated with AD pathogenesis, which is derived from the amyloid precursor protein (APP) cleavage. Recent studies suggest that synaptic activity is one of the most important factors that regulate Aβ levels. It has been found that synaptic activity facilitates APP internalization and influences APP cleavage. Glutamatergic, cholinergic, serotonergic, leptin, adrenergic, orexin, and gamma-amino butyric acid receptors, as well as the activity-regulated cytoskeleton-associated protein (Arc) are all involved in these processes. The present review summarizes the evidence for synaptic activity-modulated Aβ levels and the mechanisms underlying this regulation. Interestingly, the immediate early gene product Arc may also be the downstream signaling molecule of several receptors in the synaptic activity-modulated Aβ levels. Elucidating how Aβ levels are regulated by synaptic activity may provide new insights in both the understanding of the pathogenesis of AD and in the development of therapies to slow down the progression of AD.
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Affiliation(s)
- Xiaofang Cheng
- Department of Physiology, Third Military Medical University, Chongqing, China
| | - Jian Wu
- Department of Physiology, Third Military Medical University, Chongqing, China
| | - Miao Geng
- Institute of Geriatrics, General Hospital of Chinese PLA, Beijing, China
| | - Jiaxiang Xiong
- Department of Physiology, Third Military Medical University, Chongqing, China.
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36
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Jellinger KA, Attems J. Neuropathological approaches to cerebral aging and neuroplasticity. DIALOGUES IN CLINICAL NEUROSCIENCE 2013. [PMID: 23576887 PMCID: PMC3622466 DOI: 10.31887/dcns.2013.15.1/kjellinger] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Cerebral aging is a complex and heterogenous process related to a large variety of molecular changes involving multiple neuronal networks, due to alterations of neurons (synapses, axons, dendrites, etc), particularly affecting strategically important regions, such as hippocampus and prefrontal areas. A substantial proportion of nondemented, cognitively unimpaired elderly subjects show at least mild to moderate, and rarely even severe, Alzheimer-related lesions, probably representing asymptomatic preclinical Alzheimer's disease, and/or mixed pathologies. While the substrate of resilience to cognitive decline in the presence of abundant pathologies has been unclear, recent research has strengthened the concept of cognitive or brain reserve, based on neuroplasticity or the ability of the brain to manage or counteract age-related changes or pathologies by reorganizing its structure, connections, and functions via complex molecular pathways and mechanisms that are becoming increasingly better understood. Part of neuroplasticity is adult neurogenesis in specific areas of the brain, in particular the hippocampal formation important for memory function, the decline of which is common even in “healthy” aging. To obtain further insights into the mechanisms of brain plasticity and adult neurogenesis, as the basis for prevention and potential therapeutic options, is a major challenge of modern neurosciences.
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37
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Crimins JL, Rocher AB, Luebke JI. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol 2012; 124:777-95. [PMID: 22976049 DOI: 10.1007/s00401-012-1038-9] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 08/20/2012] [Accepted: 08/21/2012] [Indexed: 12/14/2022]
Abstract
Whole-cell patch-clamp recordings and high-resolution morphometry were used to assess functional and structural properties of layer 3 pyramidal neurons in early (<4 months) and advanced (>8 months) stages of tauopathy in frontal cortical slices prepared from rTg4510 tau mutant (P301L) mice. In early tauopathy, dendritic architecture is preserved. In advanced tauopathy, neurons can be categorized as either "atrophic" (58 %)-exhibiting marked atrophy of the apical tuft, or "intact" (42 %)-with normal apical tufts and, in some instances, proliferative sprouting of oblique branches of the apical trunk. Approximately equal numbers of atrophic and intact neurons contain neurofibrillary tangles (NFTs) or are tangle-free, lending further support to the idea that NFTs per se are not toxic. Spine density is decreased due to a specific reduction in mushroom spines, but filopodia are increased in both atrophic and intact neurons. By contrast to these morphological changes, which are robust only in the advanced stage, significant electrophysiological changes are present in the early stage and persist in the advanced stage in both atrophic and intact neurons. The most marked of these changes are: a depolarized resting membrane potential, an increased depolarizing sag potential and increased action potential firing rates-all indicative of hyperexcitability. Spontaneous excitatory postsynaptic currents are not reduced in frequency or amplitude in either stage. The difference in the time course of functionally important electrophysiological changes versus regressive morphological changes implies differences in pathogenic mechanisms underlying functional and structural changes to neurons during progressive tauopathy.
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Affiliation(s)
- Johanna L Crimins
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
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38
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Abstract
In this article, we will describe the malignant synaptic growth hypothesis of Alzheimer's disease. Originally presented in 1994, the hypothesis remains a viable model of the functional and biophysical mechanisms underlying the development and progression of Alzheimer's disease. In this article, we will refresh the model with references to relevant empirical support that has been generated in the intervening two decades since it's original presentation. We will include discussion of its relationship, in terms of points of alignment and points of contention, to other models of Alzheimer's disease, including the cholinergic hypothesis and the tau and β-amyloid models of Alzheimer's disease. Finally, we propose several falsifiable predictions made by the malignant synaptic growth hypothesis and describe the avenues of treatment that hold the greatest promise under this hypothesis.
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Affiliation(s)
- Ehren L Newman
- Center for Memory & Brain, Boston University, 2 Cummington St, Boston, MA 02215, USA
| | - Christopher F Shay
- Center for Memory & Brain, Boston University, 2 Cummington St, Boston, MA 02215, USA
| | - Michael E Hasselmo
- Center for Memory & Brain, Boston University, 2 Cummington St, Boston, MA 02215, USA
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39
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Affiliation(s)
- Didier Leys
- Department of Neurology, Stroke Unit, Roger Salengro Hospital, F-59037 Lille, France.
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40
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Liu J, Liu Y, Zou W, Song L, An L. Catalpol Upregulates Hippocampal GAP-43 Level of Aged Rats with Enhanced Spatial Memory and Behavior Response. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/jbbs.2012.24058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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41
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Wang L. Interactions between neural networks: a mechanism for tuning chaos and oscillations. Cogn Neurodyn 2011; 1:185-8. [PMID: 19003511 DOI: 10.1007/s11571-006-9004-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We show that chaos and oscillations in a higher-order binary neural network can be tuned effectively using interactions between neural networks. Our results suggest that network interactions may be useful as a means of adjusting the level of dynamic activities in systems that employ chaos and oscillations for information processing, or as a means of suppressing oscillatory behaviors in systems that require stability.
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Affiliation(s)
- Lipo Wang
- School of Electrical and Electronic Engineering, Nanyang Technological University, Block S1, Nanyang Avenue, Singapore, 639798, Singapore,
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42
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Cognitive reserve and its implications for rehabilitation and Alzheimer’s disease. Cogn Process 2011; 13:1-12. [DOI: 10.1007/s10339-011-0410-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Accepted: 05/18/2011] [Indexed: 12/14/2022]
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Howes MJR, Perry E. The Role of Phytochemicals in the Treatment and Prevention of Dementia. Drugs Aging 2011; 28:439-68. [DOI: 10.2165/11591310-000000000-00000] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Salcedo-Tello P, Ortiz-Matamoros A, Arias C. GSK3 Function in the Brain during Development, Neuronal Plasticity, and Neurodegeneration. Int J Alzheimers Dis 2011; 2011:189728. [PMID: 21660241 PMCID: PMC3109514 DOI: 10.4061/2011/189728] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 03/07/2011] [Indexed: 02/06/2023] Open
Abstract
GSK3 has diverse functions, including an important role in brain pathology. In this paper, we address the primary functions of GSK3 in development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases. Specifically, GSK3 plays a pivotal role in controlling neuronal progenitor proliferation and establishment of neuronal polarity during development, and the upstream and downstream signals modulating neuronal GSK3 function affect cytoskeletal reorganization and neuroplasticity throughout the lifespan. Modulation of GSK3 in brain areas subserving cognitive function has become a major focus for treating neuropsychiatric and neurodegenerative diseases. As a crucial node that mediates a variety of neuronal processes, GSK3 is proposed to be a therapeutic target for restoration of synaptic functioning and cognition, particularly in Alzheimer's disease.
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Affiliation(s)
- Pamela Salcedo-Tello
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, AP 70-228, 04510 Ciudad de México, Mexico
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Braak H, Del Tredici K. Alzheimer's pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol 2011; 121:589-95. [PMID: 21516512 DOI: 10.1007/s00401-011-0825-z] [Citation(s) in RCA: 261] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 04/12/2011] [Accepted: 04/12/2011] [Indexed: 01/01/2023]
Abstract
There is increasing interest in the early phase of Alzheimer's disease before severe neuronal dysfunction occurs, but it is still not known when or where in the central nervous system the underlying pathological process begins. In this review, we discuss the idea of possible disease progression from the locus coeruleus to the transentorhinal region of the cerebral cortex via neuron-to-neuron transmission and transsynaptic transport of tau protein aggregates, and we speculate that such a mechanism together with the very long prodromal period that characterizes Alzheimer's disease may be indicative of a prion-like pathogenesis for this tauopathy. The fact that AT8-immunoreactive abnormal tau aggregates (pretangles) develop within proximal axons of noradrenergic coeruleus projection neurons in the absence of both tau lesions (pretangles, NFTs/NTs) in the transentorhinal region as well as cortical amyloid-β pathology means that currently used neuropathological stages for Alzheimer's disease will have to be reclassified.
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Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol 2011; 121:171-81. [PMID: 21170538 DOI: 10.1007/s00401-010-0789-4] [Citation(s) in RCA: 587] [Impact Index Per Article: 41.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Revised: 12/07/2010] [Accepted: 12/07/2010] [Indexed: 12/15/2022]
Abstract
Brains of 42 individuals between the ages of 4 and 29 were examined with antibodies (AT8, 4G8) and silver stains for the presence of intraneuronal and extracellular protein aggregates associated with Alzheimer's disease. Thirty-eight of 42 (38/42) cases displayed abnormally phosphorylated tau protein (pretangle material) in nerve cells or in portions of their cellular processes, and 41/42 individuals showed no extracellular amyloid-β protein deposition or neuritic plaques-an individual with Down syndrome was the only exception. In 16/42 cases abnormal tau was found in the transentorhinal region, and in 3/42 cases this site was Gallyas-positive for isolated NFTs (NFT stage I). Of 26 cases that lacked abnormal tau in the transentorhinal region, 4 did not show pretangle material at subcortical sites. The remaining 22 of these same 26 cases, however, had subcortical lesions confined to non-thalamic nuclei with diffuse projections to the cerebral cortex, and, remarkably, in 19/22 individuals the pretangle material was confined to the noradrenergic coeruleus/subcoeruleus complex. Assuming the pretangle alterations are not transient and do not regress, these findings may indicate that the Alzheimer's disease-related pathological process leading to neurofibrillary tangle formation does not begin in the cerebral cortex but, rather, in select subcortical nuclei, and it may start quite early, i.e., before puberty or in early young adulthood.
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Affiliation(s)
- Heiko Braak
- Department of Neurology, Center for Clinical Research, University of Ulm, Germany.
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47
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Ashford JW, Salehi A, Furst A, Bayley P, Frisoni GB, Jack CR, Sabri O, Adamson MM, Coburn KL, Olichney J, Schuff N, Spielman D, Edland SD, Black S, Rosen A, Kennedy D, Weiner M, Perry G. Imaging the Alzheimer brain. J Alzheimers Dis 2011; 26 Suppl 3:1-27. [PMID: 21971448 PMCID: PMC3760773 DOI: 10.3233/jad-2011-0073] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This supplement to the Journal of Alzheimer's Disease contains more than half of the chapters from The Handbook of Imaging the Alzheimer Brain, which was first presented at the International Conference on Alzheimer's Disease in Paris, in July, 2011. While the Handbook contains 27 chapters that are modified articles from 2009, 2010, and 2011 issues of the Journal of Alzheimer's Disease, this supplement contains the 31 new chapters of that book and an introductory article drawn from the introductions to each section of the book. The Handbook was designed to provide a multilevel overview of the full field of brain imaging related to Alzheimer's disease (AD). The Handbook, as well as this supplement, contains both reviews of the basic concepts of imaging, the latest developments in imaging, and various discussions and perspectives of the problems of the field and promising directions. The Handbook was designed to be useful for students and clinicians interested in AD as well as scientists studying the brain and pathology related to AD.
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48
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49
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Megalin interacts with APP and the intracellular adapter protein FE65 in neurons. Mol Cell Neurosci 2010; 45:306-15. [DOI: 10.1016/j.mcn.2010.07.005] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Revised: 06/19/2010] [Accepted: 07/07/2010] [Indexed: 11/23/2022] Open
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50
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Samuel F, Hynds DL. RHO GTPase signaling for axon extension: is prenylation important? Mol Neurobiol 2010; 42:133-42. [PMID: 20878268 DOI: 10.1007/s12035-010-8144-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Accepted: 09/12/2010] [Indexed: 12/27/2022]
Abstract
Many lines of evidence indicate the importance of the Rho family guanine nucleotide triphosphatases (GTPases) in directing axon extension and guidance. The signaling networks that involve these proteins regulate actin cytoskeletal dynamics in navigating neuronal growth cones. However, the intricate patterns that regulate Rho GTPase activation and signaling are not yet fully defined. Activity and subcellular localization of the Rho GTPases are regulated by post-translational modification. The addition of a geranylgeranyl group to the carboxy (C-) terminus targets Rho GTPases to the plasma membrane and promotes their activation by facilitating interaction with guanine nucleotide exchange factors and allowing sequestering by association with guanine dissociation inhibitors. However, it is unclear how these modifications affect neurite extension or how subcellular localization alters signaling from the classical Rho GTPases (RhoA, Rac1, and Cdc42). Here, we review recent data addressing this issue and propose that Rho GTPase geranylgeranylation regulates outgrowth.
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Affiliation(s)
- Filsy Samuel
- Department of Biology, Texas Woman's University, PO Box 425799, Denton, TX 46204-5799, USA
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