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He Y, Liu B, Yang F, Yang Q, Xu B, Liu L, Chen Y. TAF15 downregulation contributes to the benefits of physical training on dendritic spines and working memory in aged mice. Aging Cell 2024; 23:e14244. [PMID: 38874013 PMCID: PMC11488317 DOI: 10.1111/acel.14244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/15/2024] [Accepted: 06/05/2024] [Indexed: 06/15/2024] Open
Abstract
Moderate physical training has been shown to hinder age-related memory decline. While the benefits of physical training on hippocampal memory function are well-documented, little is known about its impact on working memory, which is linked to the prelimbic cortex (PrL), one major subdivision of the prefrontal cortex. Here, we examined the effects of physical training on spatial working memory in a well-established animal model of physical training, starting at 16 months of age and continuing for 5 months (running wheel 1 h/day and 5 days/week). This training strategy improved spatial working memory in aged mice (22-month-old), which was accompanied by an increased spine density and a lower TAF15 expression in the PrL. Specifically, physical training affected both thin and mushroom-type spines on PrL pyramidal cells, and prevented age-related loss of spines on selective segments of apical dendritic branches. Correlation analysis revealed that increased TAF15-expression was detrimental to the dendritic spines. However, physical training downregulated TAF15 expression in the PrL, preserving the dendritic spines on PrL pyramidal cells and improving working memory in trained aged mice. When TAF15 was overexpressed in the PrL via a viral approach, the benefits of physical training on the dendritic spines and working memory were abolished. These data suggest that physical training at a moderate pace might downregulate TAF15 expression in the PrL, which favors the dendritic spines on PrL pyramidal cells, thereby improving spatial working memory.
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Affiliation(s)
- Yun He
- Department of Anatomy, School of MedicineYangtze UniversityJingzhouChina
| | - Benju Liu
- Department of Anatomy, School of MedicineYangtze UniversityJingzhouChina
| | - Fu‐Yuan Yang
- Health Science CenterYangtze UniversityJingzhouChina
| | - Qun Yang
- Department of Medical Imaging, School of MedicineYangtze UniversityJingzhouChina
| | - Benke Xu
- Department of Anatomy, School of MedicineYangtze UniversityJingzhouChina
| | - Lian Liu
- Department of Pharmacology, School of MedicineYangtze UniversityJingzhouChina
| | - Yuncai Chen
- Department of Anatomy, School of MedicineYangtze UniversityJingzhouChina
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Santoro B, Srinivas KV, Reyes I, Tian C, Masurkar AV. Cell type-specific impact of aging and Alzheimer disease on hippocampal CA1 perforant path input. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.27.609952. [PMID: 39253428 PMCID: PMC11383042 DOI: 10.1101/2024.08.27.609952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
The perforant path (PP) carries direct inputs from entorhinal cortex to CA1 pyramidal neurons (PNs), with an impact dependent on PN position across transverse (CA1a-CA1c) and radial (superficial/deep) axes. It remains unclear how aging and Alzheimer disease (AD) affect PP input, despite its critical role in memory and early AD. Applying ex vivo recordings and two-photon microscopy in slices from mice up to 30 months old, we interrogated PP responses across PN subpopulations and compared them to Schaffer collateral and intrinsic excitability changes. We found that aging uniquely impacts PP excitatory responses, abolishing transverse and radial differences via a mechanism independent of presynaptic and membrane excitability change. This is amplified in aged 3xTg-AD mice, with further weakening of PP inputs to CA1a superficial PNs associated with distal dendritic spine loss. This demonstrates a unique feature of aging-related circuit dysfunction, with mechanistic implications related to memory impairment and synaptic vulnerability.
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Wang Y, Zheng AN, Yang H, Wang Q, Dai B, Wang JJ, Wan YT, Liu ZB, Liu SY. Olfactory Three-Needle Electroacupuncture Improved Synaptic Plasticity and Gut Microbiota of SAMP8 Mice by Stimulating Olfactory Nerve. Chin J Integr Med 2024; 30:729-741. [PMID: 37999886 DOI: 10.1007/s11655-023-3614-3] [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] [Accepted: 06/07/2023] [Indexed: 11/25/2023]
Abstract
OBJECTIVE To investigate the effects and mechanisms of olfactory three-needle (OTN) electroacupuncture (EA) stimulation of the olfactory system on cognitive dysfunction, synaptic plasticity, and the gut microbiota in senescence-accelerated mouse prone 8 (SAMP8) mice. METHODS Thirty-six SAMP8 mice were randomly divided into the SAMP8 (P8), SAMP8+OTN (P8-OT), and SAMP8+nerve transection+OTN (P8-N-OT) groups according to a random number table (n=12 per group), and 12 accelerated senescence-resistant (SAMR1) mice were used as the control (R1) group. EA was performed at the Yintang (GV 29) and bilateral Yingxiang (LI 20) acupoints of SAMP8 mice for 4 weeks. The Morris water maze test, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, Nissl staining, Golgi staining, Western blot, and 16S rRNA sequencing were performed, respectively. RESULTS Compared with the P8 group, OTN improved the cognitive behavior of SAMP8 mice, inhibited neuronal apoptosis, increased neuronal activity, and attenuated hippocampal synaptic dysfunction (P<0.05 or P<0.01). Moreover, the expression levels of synaptic plasticity-related proteins N-methyl-D-aspartate receptor 1 (NMDAR1), NMDAR2B, synaptophysin (SYN), and postsynaptic density protein-95 (PSD95) in hippocampus were increased by OTN treatment (P<0.05 or P<0.01). Furthermore, OTN greatly enhanced the brain-derived neurotrophic factor (BDNF)/cAMP-response element binding (CREB) signaling and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling compared with the P8 group (P<0.05 or P<0.01). However, the neuroprotective effect of OTN was attenuated by olfactory nerve truncation. Compared with the P8 group, OTN had a very limited effect on the fecal microbial structure and composition of SAMP8 mice, while specifically increased the genera Oscillospira and Sutterella (P<0.05). Interestingly, the P8-N-OT group showed an abnormal fecal microbiota with higher microbial α-diversity, Firmicutes/Bacteroidetes ratio and pathogenic bacteria (P<0.05 or P<0.01). CONCLUSIONS OTN improved cognitive deficits and hippocampal synaptic plasticity by stimulating the olfactory nerve and activating the BDNF/CREB and PI3K/AKT/mTOR signaling pathways. Although the gut microbiota was not the main therapeutic target of OTN for Alzheimer's disease, the olfactory nerve was essential to maintain the homeostasis of gut microbiota.
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Affiliation(s)
- Yuan Wang
- College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
- Shaanxi Key Laboratory of Acupuncture and Medicine, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
| | - A-Ni Zheng
- Shaanxi Key Laboratory of Acupuncture and Medicine, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712000, China
| | - Huan Yang
- Department of Traditional Chinese Medicine, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, 014040, China
| | - Qiang Wang
- College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
- Shaanxi Key Laboratory of Acupuncture and Medicine, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
| | - Biao Dai
- College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
| | - Jia-Ju Wang
- College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
| | - Yi-Tong Wan
- College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
| | - Zhi-Bin Liu
- College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
- Shaanxi Key Laboratory of Acupuncture and Medicine, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, China
| | - Si-Yang Liu
- School of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China.
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Lee JY, Jeong EA, Lee J, Shin HJ, Lee SJ, An HS, Kim KE, Kim WH, Bae YC, Kang H, Roh GS. TonEBP Haploinsufficiency Attenuates Microglial Activation and Memory Deficits in Middle-Aged and Amyloid β Oligomer-Treated Mice. Cells 2023; 12:2612. [PMID: 37998347 PMCID: PMC10670066 DOI: 10.3390/cells12222612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023] Open
Abstract
Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)-injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells. Consistent with an increase in microglial activation with aging, hippocampal TonEBP expression levels were increased in middle-aged (12-month-old) and old (24-month-old) mice compared with young (6-month-old) mice. Middle-aged TonEBP haploinsufficient mice showed reduced microglial activation and fewer memory deficits than wild-type mice. Electron microscopy revealed that synaptic pruning by microglial processes was reduced by TonEBP haploinsufficiency. TonEBP haploinsufficiency also reduced dendritic spine loss and improved memory deficits in AβO-treated mice. Furthermore, TonEBP knockdown attenuated migration and phagocytosis in AβO-treated BV2 cells. These findings suggest that TonEBP plays important roles in age-related microglial activation and memory deficits.
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Affiliation(s)
- Jong Youl Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
- Division of Cardiovascular Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju 28159, Republic of Korea;
| | - Eun Ae Jeong
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
| | - Jaewoong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
| | - Hyun Joo Shin
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
| | - So Jeong Lee
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
| | - Hyeong Seok An
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
| | - Kyung Eun Kim
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
| | - Won-Ho Kim
- Division of Cardiovascular Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju 28159, Republic of Korea;
| | - Yong Chul Bae
- Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41944, Republic of Korea;
| | - Heeyoung Kang
- Department of Neurology, College of Medicine, Gyeongsang National University Hospital, Gyeongsang National University, Jinju 52727, Republic of Korea;
| | - Gu Seob Roh
- Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.L.); (E.A.J.); (J.L.); (H.J.S.); (S.J.L.); (H.S.A.); (K.E.K.)
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Yang J, Yuan S, Jian Y, Lei Y, Hu Z, Yang Q, Yan X, Zheng L, Li J, Liu W. Aerobic exercise regulates GPR81 signal pathway and mediates complement- microglia axis homeostasis on synaptic protection in the early stage of Alzheimer's disease. Life Sci 2023; 331:122042. [PMID: 37634815 DOI: 10.1016/j.lfs.2023.122042] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/07/2023] [Accepted: 08/23/2023] [Indexed: 08/29/2023]
Abstract
AIMS Memory impairment is a major clinical manifestation in Alzheimer's disease (AD) patients, while regular exercise may prevent and delay degenerative changes in memory functions, and our aim is to explore the influence and molecular mechanisms of aerobic exercise on the early stages of Alzheimer's disease. MAIN METHODS 3-month-old male APP/PS1 transgenic AD mice and C57BL/6J wild-type mice were randomly divided into four groups: wild-type and APP/PS1 mice with sedentary (WT-SED, AD-SED), and running (WT-RUN, AD-RUN) for 12-weeks. The spatial learning and memory function, RNA-sequencing, spine density, synaptic associated protein, mRNA and protein expression involved in G protein-coupled receptor 81 (GPR81) signaling pathway, and complement factors in brain were measured. KEY FINDINGS Aerobic exercise improved spatial learning and memory in APP/PS1 mice, potentially attributed to increased dendritic spine density. Subsequently, potential underlying mechanisms were identified through RNA sequencing: regular aerobic exercise could activate the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cAMP/PKA signaling pathway and upregulate synaptic function-related proteins to promote synaptic growth, possibly by modulating GPR81. Notably, regular aerobic exercise inhibited microglial activation, reversed the microglial phenotype, reduced the production of initiation factor C1q and central factor C3 in the complement cascade in the brain, prevented the colocalization of microglia and PSD-95, and thus prevented synaptic loss. SIGNIFICANCE Physical exercise could play a critical role in improving cognitive function in AD by promoting synaptic growth and preventing synaptic loss, which may be related to the regulation of the GPR81/cAMP/PKA signaling pathway and inhibition of complement-mediated microglial phagocytosis of synapses.
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Affiliation(s)
- Jialun Yang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Shunling Yuan
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Ye Jian
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Yong Lei
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Zelin Hu
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Qiming Yang
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Xinjun Yan
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Lan Zheng
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China
| | - Jianghua Li
- College of Physical Education, Jiangxi Normal University, Nanchang 330022, China
| | - Wenfeng Liu
- Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha 410012, China; Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, Hunan Normal University, Changsha 410081, China.
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Xu L, Liu Y, Long J, He X, Xie F, Yin Q, Chen M, Long D, Chen Y. Loss of spines in the prelimbic cortex is detrimental to working memory in mice with early-life adversity. Mol Psychiatry 2023; 28:3444-3458. [PMID: 37500828 PMCID: PMC10618093 DOI: 10.1038/s41380-023-02197-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 07/29/2023]
Abstract
Adverse experiences in early life can shape neuronal structures and synaptic function in multiple brain regions, leading to deficits of distinct cognitive functions later in life. Focusing on the pyramidal cells of the prelimbic cortex (PrL), a main subregion of the medial prefrontal cortex, the impact of early-life adversity (ELA) was investigated in a well-established animal model generated by changing the rearing environment during postnatal days 2 to 9 (P2-P9), a sensitive developmental period. ELA has enduring detrimental impacts on the dendritic spines of PrL pyramidal cells, which is most apparent in a spatially circumscribed region. Specifically, ELA affects both thin and mushroom-type spines, and ELA-provoked loss of spines is observed on selective dendritic segments of PrL pyramidal cells in layers II-III and V-VI. Reduced postsynaptic puncta represented by postsynaptic density protein-95 (PSD-95), but not synaptophysin-labelled presynaptic puncta, in ELA mice supports the selective loss of spines in the PrL. Correlation analysis indicates that loss of spines and postsynaptic puncta in the PrL contributes to the poor spatial working memory of ELA mice, and thin spines may play a major role in working memory performance. To further understand whether loss of spines affects glutamatergic transmission, AMPA- and NMDA-receptor-mediated synaptic currents (EPSCs) were recorded in a group of Thy1-expressing PrL pyramidal cells. ELA mice exhibited a depressed glutamatergic transmission, which is accompanied with a decreased expression of GluR1 and NR1 subunits in the PrL. Finally, upregulating the activation of Thy1-expressing PrL pyramidal cells via excitatory DREADDs can efficiently improve the working memory performance of ELA mice in a T-maze-based task, indicating the potential of a chemogenetic approach in restoring ELA-provoked memory deficits.
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Affiliation(s)
- Liping Xu
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Yue Liu
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Jingyi Long
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525GA, Nijmegen, the Netherlands
| | - Xiulan He
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Fanbing Xie
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Qiao Yin
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Michael Chen
- University of California, Los Angeles, CA, 90095, USA
| | - Dahong Long
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
| | - Yuncai Chen
- Department of Pediatrics, University of California, Irvine, CA, 92697, USA.
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Britton R, Wasley T, Harish R, Holz C, Hall J, Yee DC, Melton Witt J, Booth EA, Braithwaite S, Czirr E, Kerrisk Campbell M. Noncanonical Activity of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) Improves Cognition and Synapse Density in Aging. eNeuro 2023; 10:ENEURO.0031-23.2023. [PMID: 37321845 PMCID: PMC10275401 DOI: 10.1523/eneuro.0031-23.2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/01/2023] [Accepted: 05/14/2023] [Indexed: 06/17/2023] Open
Abstract
Peripheral administration of tissue inhibitor of metalloproteinases 2 (TIMP2), a protein inhibitor of matrix metalloproteinases (MMPs), has previously been shown to have beneficial effects on cognition and neurons in aged mice. Here, to better understand the potential of recombinant TIMP2 proteins, an IgG4Fc fusion protein (TIMP2-hIgG4) was developed to extend the plasma half-life of TIMP2. Following one month of administration of TIMP2 or TIMP2-hIgG4 via intraperitoneal injections, 23-month-old male C57BL/6J mice showed improved hippocampal-dependent memory in a Y-maze, increased hippocampal cfos gene expression, and increased excitatory synapse density in the CA1 and dentate gyrus (DG) of the hippocampus. Thus, fusion to hIgG4 extended the half-life of TIMP2 while retaining the beneficial cognitive and neuronal effects. Moreover, it retained its ability to cross the blood-brain barrier. To deepen the mechanistic understanding of the beneficial function of TIMP2 on neuronal activity and cognition, a TIMP2 construct lacking MMP inhibitory activity, Ala-TIMP2, was generated, which provides steric hindrance that prevents inhibition of MMPs by the TIMP2 protein while still allowing MMP binding. A comprehensive assessment of the MMP inhibitory and binding capacity of these engineered proteins is outlined. Surprisingly, MMP inhibition by TIMP2 was not essential for its beneficial effects on cognition and neuronal function. These findings both confirm previously published research, expand on the potential mechanism for the beneficial effects of TIMP2, and provide important details for a therapeutic path forward for TIMP2 recombinant proteins in aging-related cognitive decline.
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Affiliation(s)
| | - Tristan Wasley
- Grifols Diagnostic Solutions, Inc., Emeryville, CA 94608
| | | | - Charles Holz
- Grifols Diagnostic Solutions, Inc., Emeryville, CA 94608
| | - John Hall
- Grifols Diagnostic Solutions, Inc., Emeryville, CA 94608
| | - Dennis C Yee
- Grifols Diagnostic Solutions, Inc., Emeryville, CA 94608
| | | | | | | | - Eva Czirr
- Alkahest, Inc., San Carlos, CA 94070
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Zhang Z, Chen L, Guo Y, Li D, Zhang J, Liu L, Fan W, Guo T, Qin S, Zhao Y, Xu Z, Chen Z. The neuroprotective and neural circuit mechanisms of acupoint stimulation for cognitive impairment. Chin Med 2023; 18:8. [PMID: 36670425 PMCID: PMC9863122 DOI: 10.1186/s13020-023-00707-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 12/30/2022] [Indexed: 01/21/2023] Open
Abstract
Cognitive impairment is a prevalent neurological disorder that burdens families and the healthcare system. Current conventional therapies for cognitive impairment, such as cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists, are unable to completely stop or reverse the progression of the disease. Also, these medicines may cause serious problems with the digestive system, cardiovascular system, and sleep. Clinically, stimulation of acupoints has the potential to ameliorate the common symptoms of a variety of cognitive disorders, such as memory deficit, language dysfunction, executive dysfunction, reduced ability to live independently, etc. There are common acupoint stimulation mechanisms for treating various types of cognitive impairment, but few systematic analyses of the underlying mechanisms in this domain have been performed. This study comprehensively reviewed the basic research from the last 20 years and found that acupoint stimulation can effectively improve the spatial learning and memory of animals. The common mechanism may be that acupoint stimulation protects hippocampal neurons by preventing apoptosis and scavenging toxic proteins. Additionally, acupoint stimulation has antioxidant and anti-inflammatory effects, promoting neural regeneration, regulating synaptic plasticity, and normalizing neural circuits by restoring brain functional activity and connectivity. Acupoint stimulation also inhibits the production of amyloid β-peptide and the phosphorylation of Tau protein, suggesting that it may protect neurons by promoting correct protein folding and regulating the degradation of toxic proteins via the autophagy-lysosomal pathway. However, the benefits of acupoint stimulation still need to be further explored in more high-quality studies in the future.
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Affiliation(s)
- Zichen Zhang
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China
| | - Liuyi Chen
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.257143.60000 0004 1772 1285First Clinical College, Hubei University of Chinese Medicine, Wuhan, 430065 People’s Republic of China
| | - Yi Guo
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381 People’s Republic of China
| | - Dan Li
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218School of Acupuncture and Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381 People’s Republic of China
| | - Jingyu Zhang
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China
| | - Ling Liu
- grid.257143.60000 0004 1772 1285First Clinical College, Hubei University of Chinese Medicine, Wuhan, 430065 People’s Republic of China
| | - Wen Fan
- grid.412879.10000 0004 0374 1074Department of Rehabilitation Physical Therapy Course, Faculty of Health Science, Suzuka University of Medical Science, Suzuka City, 5100293 Japan
| | - Tao Guo
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China
| | - Siru Qin
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China
| | - Yadan Zhao
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China
| | - Zhifang Xu
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218School of Acupuncture and Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381 People’s Republic of China
| | - Zelin Chen
- grid.410648.f0000 0001 1816 6218Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218School of Acupuncture and Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 People’s Republic of China ,grid.410648.f0000 0001 1816 6218National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381 People’s Republic of China
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9
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Wang Y, Xu N, Wang R, Zai W. Systematic review and network meta-analysis of effects of noninvasive brain stimulation on post-stroke cognitive impairment. Front Neurosci 2022; 16:1082383. [PMID: 36643019 PMCID: PMC9832390 DOI: 10.3389/fnins.2022.1082383] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/05/2022] [Indexed: 12/29/2022] Open
Abstract
Objective To systematically assess the effects of Noninvasive Brain Stimulation (NIBS) on post-stroke cognitive impairment (PSCI) and to compare the efficacy of two different NIBS. Methods Computer searches of PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Chinese Biomedical literature Service System (SinoMed), and Wanfang Database were conducted using a combination of free words and subject terms. The search was conducted from the database creation date to 27 November 2022. The risk of bias in the included literature was assessed using the Cochrane Risk Assessment Scale. The quality of the included literature was assessed using the physiotherapy evidence database (PEDro) scale. A standard meta-analysis of study data for each outcome indicator was performed using RevMan 5.4 software. Network meta-analysis was performed using State 14.0 according to the Bayesian framework. Results A total of 18 studies involving 809 patients were included. Meta-analysis shows NIBS significantly improved montreal cognitive assessment (MoCA) scores (standardized mean difference [SMD] = 0.76, 95% confidence interval (CI) 0.49-1.02, P < 0.05), mini-mental state examination (MMSE) scores (SMD = 0.72, 95% CI 0.25-1.20, P < 0.05), and modified barthel index (MBI) and functional independence measurement (FIM) scores (SMD = 0.33, 95% CI 0.11-0.54, P < 0.05) in patients with PSCI. The surface under the cumulative ranking curve (SUCRA) of different NIBS in improving MoCA scores were in the order of transcranial direct current stimulation (tDCS) (SUCRA = 92.4%) and transcranial magnetic stimulation (TMS) (SUCRA = 57.6%). The SUCRA of different NIBS in improving MMSE scores were in the order of tDCS (SUCRA = 81.6%) and TMS (SUCRA = 67.3%). The SUCRA of different NIBS in improving MBI and FIM scores were in the order of tDCS (SUCRA = 78.6%) and TMS (SUCRA = 65.3%). Conclusion The available evidence suggests that NIBS improves cognitive impairment. tDCS appeared more effective than TMS for cognitive function and activities of daily living in PSCI patients. Limited by the number of included studies, more large-sample, multicentre, double-blind, high-quality randomized controlled clinical trials are needed to further confirm this study's results. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier: CRD42022372354.
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10
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Cohen LD, Ziv T, Ziv NE. Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points. Front Mol Neurosci 2022; 15:1038614. [PMID: 36583084 PMCID: PMC9792512 DOI: 10.3389/fnmol.2022.1038614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/07/2022] [Indexed: 12/14/2022] Open
Abstract
Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential 'early-lost' proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer's disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.
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Affiliation(s)
- Laurie D. Cohen
- Technion Faculty of Medicine, Rappaport Institute and Network Biology Research Laboratories, Haifa, Israel
| | - Tamar Ziv
- Smoler Proteomics Center, Lokey Interdisciplinary Center for Life Sciences & Engineering, Technion, Haifa, Israel
| | - Noam E. Ziv
- Technion Faculty of Medicine, Rappaport Institute and Network Biology Research Laboratories, Haifa, Israel,*Correspondence: Noam E. Ziv,
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11
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Britton R, Liu AT, Rege SV, Adams JM, Akrapongpisak L, Le D, Alcantara-Lee R, Estrada RA, Ray R, Ahadi S, Gallager I, Yang CF, Minami SS, Braithwaite SP, Czirr E, Campbell MK. Molecular and histological correlates of cognitive decline across age in male C57BL/6J mice. Brain Behav 2022; 12:e2736. [PMID: 35971662 PMCID: PMC9480918 DOI: 10.1002/brb3.2736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 07/01/2022] [Accepted: 07/20/2022] [Indexed: 11/09/2022] Open
Abstract
INTRODUCTION Increasing age is the number one risk factor for developing cognitive decline and neurodegenerative disease. Aged humans and mice exhibit numerous molecular changes that contribute to a decline in cognitive function and increased risk of developing age-associated diseases. Here, we characterize multiple age-associated changes in male C57BL/6J mice to understand the translational utility of mouse aging. METHODS Male C57BL/6J mice from various ages between 2 and 24 months of age were used to assess behavioral, as well as, histological and molecular changes across three modalities: neuronal, microgliosis/neuroinflammation, and the neurovascular unit (NVU). Additionally, a cohort of 4- and 22-month-old mice was used to assess blood-brain barrier (BBB) breakdown. Mice in this cohort were treated with a high, acute dose of lipopolysaccharide (LPS, 10 mg/kg) or saline control 6 h prior to sacrifice followed by tail vein injection of 0.4 kDa sodium fluorescein (100 mg/kg) 2 h later. RESULTS Aged mice showed a decline in cognitive and motor abilities alongside decreased neurogenesis, proliferation, and synapse density. Further, neuroinflammation and circulating proinflammatory cytokines were increased in aged mice. Additionally, we found changes at the BBB, including increased T cell infiltration in multiple brain regions and an exacerbation in BBB leakiness following chemical insult with age. There were also a number of readouts that were unchanged with age and have limited utility as markers of aging in male C57BL/6J mice. CONCLUSIONS Here we propose that these changes may be used as molecular and histological readouts that correspond to aging-related behavioral decline. These comprehensive findings, in the context of the published literature, are an important resource toward deepening our understanding of normal aging and provide an important tool for studying aging in mice.
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Affiliation(s)
| | - Angela T Liu
- Alkahest, Inc., San Carlos, California, USA.,Coda Biotherapeutics, South San Francisco, California, USA
| | | | | | - Lily Akrapongpisak
- Alkahest, Inc., San Carlos, California, USA.,University of Queensland, Herston, Queensland, Australia
| | - David Le
- Alkahest, Inc., San Carlos, California, USA.,Fountain Therapeutics, South San Francisco, California, USA
| | | | | | - Rebecca Ray
- Alkahest, Inc., San Carlos, California, USA.,202 Chives Way, Walnut Creek, California, USA
| | - Sara Ahadi
- Alkahest, Inc., San Carlos, California, USA
| | | | | | | | | | - Eva Czirr
- Alkahest, Inc., San Carlos, California, USA.,Confluence Therapeutics, South San Francisco, California, USA
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12
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Carpanini SM, Torvell M, Bevan RJ, Byrne RAJ, Daskoulidou N, Saito T, Saido TC, Taylor PR, Hughes TR, Zelek WM, Morgan BP. Terminal complement pathway activation drives synaptic loss in Alzheimer's disease models. Acta Neuropathol Commun 2022; 10:99. [PMID: 35794654 PMCID: PMC9258209 DOI: 10.1186/s40478-022-01404-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/29/2022] [Indexed: 11/23/2022] Open
Abstract
Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimer's disease. It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and AppNL-G-F Alzheimer's disease model mouse brains at 3, 6, 9 and 12 months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer's disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in AppNL-G-F mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to AppNL-G-F mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer's disease mice involving the activation (C1q; C3b/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer's disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.
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Affiliation(s)
- Sarah M Carpanini
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Megan Torvell
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Ryan J Bevan
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Robert A J Byrne
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Nikoleta Daskoulidou
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Takashi Saito
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takaomi C Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan
| | - Philip R Taylor
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Timothy R Hughes
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Wioleta M Zelek
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - B Paul Morgan
- UK Dementia Research Institute Cardiff, and Systems Immunity Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
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13
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Kuijpers M. Keeping synapses in shape: degradation pathways in the healthy and aging brain. Neuronal Signal 2022; 6:NS20210063. [PMID: 35813265 PMCID: PMC9208270 DOI: 10.1042/ns20210063] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022] Open
Abstract
Synapses maintain their molecular composition, plasticity and function through the concerted action of protein synthesis and removal. The complex and polarized neuronal architecture poses specific challenges to the logistics of protein and organelle turnover since protein synthesis and degradation mainly happen in the cell soma. In addition, post-mitotic neurons accumulate damage over a lifetime, challenging neuronal degradative pathways and making them particularly susceptible to the effects of aging. This review will summarize the current knowledge on neuronal protein turnover mechanisms with a particular focus on the presynapse, including the proteasome, autophagy and the endolysosomal route and their roles in regulating presynaptic proteostasis and function. In addition, the author will discuss how physiological brain aging, which entails a progressive decline in cognitive functions, affects synapses and the degradative machinery.
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Affiliation(s)
- Marijn Kuijpers
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, Nijmegen, The Netherlands
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14
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Xu B, Zhang X, He Y, Liu C, Li L, Liu Q, Huang Y, Chen M, Ren B, Guo Y, Chen Y. The impacts of early-life adversity on striatal and hippocampal memory functions. Neuroscience 2022; 490:11-24. [DOI: 10.1016/j.neuroscience.2022.02.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/02/2022] [Accepted: 02/25/2022] [Indexed: 12/15/2022]
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15
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Xu B, He Y, Liu L, Ye G, Chen L, Wang Q, Chen M, Chen Y, Long D. The Effects of Physical Running on Dendritic Spines and Amyloid-beta Pathology in 3xTg-AD Male Mice. Aging Dis 2022; 13:1293-1310. [PMID: 35855335 PMCID: PMC9286906 DOI: 10.14336/ad.2022.0110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/10/2022] [Indexed: 11/01/2022] Open
Abstract
Memory loss is the key symptom of Alzheimer's disease (AD). As successful drug treatments have not yet been identified, non-pharmaceutical interventions such as physical exercise and training have been employed to improve the memory function of people with dementia. We investigated the effect of prolonged physical running on hippocampal-dependent spatial memory and its underlying mechanisms using a well-established rodent model of AD. 3xTg-AD transgenic mice and non-transgenic mice were subjected to voluntary wheel running for 5 months (1 hour per day, 5 days per week), followed by spatial memory testing. After the behavioral testing, dendritic spines, synapses, and synaptic proteins as well as amyloid-beta (Aβ) pathology were analyzed in the dorsal hippocampi. Running improved hippocampal-dependent spatial memory in 3xTg-AD mice. This running strategy prevented both thin and mushroom-type spines on CA1 pyramidal cells in 3xTg-AD mice, whereas the effects of running in non-transgenic mice were limited to thin spines. The enormous effects of running on spines were accompanied by an increased number of synapses and upregulated expression of synaptic proteins. Notably, running downregulated the processing of amyloid precursor protein, decreasing intracellular APP expression and extracellular Aβ accumulation, and spatial memory performance correlated with levels of Aβ peptides Aβ1-40 and Aβ1-42. These data suggest that prolonged running may improve memory in preclinical AD via slowing down the amyloid pathology and preventing the loss of synaptic contacts.
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Affiliation(s)
- Benke Xu
- Department of Human Anatomy, School of Basic Medical Sciences, Yangtze University, Hubei 434023, China.
| | - Yun He
- Department of Human Anatomy, School of Basic Medical Sciences, Yangtze University, Hubei 434023, China.
| | - Lian Liu
- Department of Pharmacology, School of Basic Medical Sciences, Yangtze University, Hubei 434023, China.
| | - Guosheng Ye
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Lulu Chen
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Qingning Wang
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Michael Chen
- University of California, Los Angeles, CA 90095, USA.
| | - Yuncai Chen
- Department of Pediatrics, University of California, Irvine, CA 92697, USA.
- Correspondence should be addressed to: Dr. Dahong Long, Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. E-mail: or Dr. Yuncai Chen, Department of Pediatrics, University of California-Irvine, Irvine, California 92697, USA. E-mail:
| | - Dahong Long
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
- Correspondence should be addressed to: Dr. Dahong Long, Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. E-mail: or Dr. Yuncai Chen, Department of Pediatrics, University of California-Irvine, Irvine, California 92697, USA. E-mail:
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16
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The aging mouse brain: cognition, connectivity and calcium. Cell Calcium 2021; 94:102358. [PMID: 33517250 DOI: 10.1016/j.ceca.2021.102358] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 02/08/2023]
Abstract
Aging is a complex process that differentially impacts multiple cognitive, sensory, neuronal and molecular processes. Technological innovations now allow for parallel investigation of neuronal circuit function, structure and molecular composition in the brain of awake behaving adult mice. Thus, mice have become a critical tool to better understand how aging impacts the brain. However, a more granular systems-based approach, which considers the impact of age on key features relating to neural processing, is required. Here, we review evidence probing the impact of age on the mouse brain. We focus on a range of processes relating to neuronal function, including cognitive abilities, sensory systems, synaptic plasticity and calcium regulation. Across many systems, we find evidence for prominent age-related dysregulation even before 12 months of age, suggesting that emerging age-related alterations can manifest by late adulthood. However, we also find reports suggesting that some processes are remarkably resilient to aging. The evidence suggests that aging does not drive a parallel, linear dysregulation of all systems, but instead impacts some processes earlier, and more severely, than others. We propose that capturing the more fine-scale emerging features of age-related vulnerability and resilience may provide better opportunities for the rejuvenation of the aged brain.
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17
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He Y, Xu B, Chen Y, Liu L, Xu L, Chen Y, Long D. Early-life adversity selectively interrupts the dendritic differentiation of dorsolateral striatal neurons in male mice. Brain Struct Funct 2021; 226:397-414. [PMID: 33386419 DOI: 10.1007/s00429-020-02183-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 11/24/2020] [Indexed: 01/04/2023]
Abstract
The effects of early-life adversity (ELA) on dendritic differentiation of striatal neurons were investigated in the dorsal striatum including the dorsomedial striatum and dorsolateral striatum (DMS and DLS, respectively). An animal model of ELA was created by changing the growth environment of newborn mouse pups by giving limited bedding and nesting materials from postnatal day 2 to day 9 (P2-P9). One week after the stress paradigm (P16), the dendritic branches and spines of striatal spiny neurons as well as the synapses represented by postsynaptic density protein-95 (PSD-95) in DMS and DLS were stereologically analyzed. Adverse experience in early life selectively affected the spiny neurons in DLS, leading to abundant proximal dendritic branches and an increased number of filopodia-like protrusions, but a reduced number of dendritic spines. The selective effects of stress on neurons in DLS were further identified by reduced expression of PSD-95, including a reduced optical density of PSD-95 immunoreactivity and fewer individual PSD-95 immunoreactive synapses in this region. Notably, stress in early life affected either D1 or D2 dopamine receptor-expressing DLS neurons. These findings suggest that adverse early-life experience delayed the maturation of dendritic spines on neurons in the dorsolateral striatum. Altered dendritic differentiation provoked by stress in early life may contribute critically to the formation of proper neuronal circuits in the dorsal striatum and, therefore, affect striatum-dependent habitual behavior and emotional function later in life.
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Affiliation(s)
- Yun He
- Department of Human Anatomy, School of Basic Medical Sciences, Yangtze University, Hubei, 434023, China
| | - Benke Xu
- Department of Human Anatomy, School of Basic Medical Sciences, Yangtze University, Hubei, 434023, China.,Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Hubei, 434020, China
| | - Yan Chen
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangdong, 510260, China
| | - Lian Liu
- Department of Medical Function, School of Basic Medical Sciences, Yangtze University, Hubei, 434023, China
| | - Liping Xu
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yuncai Chen
- Department of Pediatrics, University of California, Irvine, CA, 92697, USA.
| | - Dahong Long
- Key Lab of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
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18
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Zhao L, Liu JW, Kan BH, Shi HY, Yang LP, Liu XY. Acupuncture accelerates neural regeneration and synaptophysin production after neural stem cells transplantation in mice. World J Stem Cells 2020; 12:1576-1590. [PMID: 33505601 PMCID: PMC7789117 DOI: 10.4252/wjsc.v12.i12.1576] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 09/23/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Synaptophysin plays a key role in synaptic development and plasticity of neurons and is closely related to the cognitive process of Alzheimer’s disease (AD) patients. Exogenous neural stem cells (NSCs) improve the damaged nerve function. The effects of Sanjiao acupuncture on cognitive impairment may be related to the regulation of the NSC microenvironment.
AIM To explore the anti-dementia mechanism of acupuncture by regulating the NSC microenvironment.
METHODS NSCs were isolated from pregnant senescence-accelerated mouse resistant 1 (SAMR1) mice, labeled with BrdU, and injected into the hippocampus of senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old senescence-accelerated mice (SAM) were randomly divided into six groups: SAMR1 (RC), SAMP8 (PC), sham transplantation (PS), NSC transplantation (PT), NSC transplantation with acupuncture (PTA), and NSC transplantation with non-acupoint acupuncture (PTN). Morris water maze test was used to study the learning and memory ability of mice after NSC transplantation. Hematoxylin-eosin staining and immunofluorescence were used to observe the his-topathological changes and NSC proliferation in mice. A co-culture model of hippocampal slices and NSCs was established in vitro, and the synaptophysin expression in the hippocampal microenvironment of mice was observed by flow cytometry after acupuncture treatment.
RESULTS Morris water maze test showed significant cognitive impairment of learning and memory in 8-mo-old SAMP8, which improved in all the NSC transplantation groups. The behavioral change in the PTA group was stronger than those in the other two groups (P < 0.05). Histopathologically, the hippocampal structure was clear, the cell arrangement was dense and orderly, and the necrosis of cells in CA1 and CA3 areas was significantly reduced in the PTA group when compared with the PC group. The BrdU-positive proliferating cells were found in NSC hippocampal transplantation groups, and the number increased significantly in the PTA group than in the PT and PTN groups (P < 0.05). Flow cytometry showed that after co-culture of NSCs with hippocampal slices in vitro, the synaptophysin expression in the PC group decreased in comparison to the RC group, that in PT, PTA, and PTN groups increased as compared to the PC group, and that in the PTA group increased significantly as compared to the PTN group with acupoint-related specificity (P < 0.05).
CONCLUSION Acupuncture may promote nerve regeneration and synaptogenesis in SAMP8 mice by regulating the microenvironment of NSC transplantation to improve the nerve activity and promote the recovery of AD-damaged cells.
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Affiliation(s)
- Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Jian-Wei Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Bo-Hong Kan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Hui-Yan Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Lin-Po Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Xin-Yu Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
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19
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Bevan RJ, Hughes TR, Williams PA, Good MA, Morgan BP, Morgan JE. Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer's disease. Acta Neuropathol Commun 2020; 8:216. [PMID: 33287900 PMCID: PMC7720390 DOI: 10.1186/s40478-020-01094-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023] Open
Abstract
Neuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer's disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer's disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer's progression. However, the extent of retinal involvement in Alzheimer's models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer's mouse models, Tg2576, 3xTg-AD and APPNL-G-F. Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer's models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer's models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer's disease.
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Affiliation(s)
- Ryan J Bevan
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
- UK Dementia Research Institute, Cardiff University, Cardiff, UK
| | - Tim R Hughes
- UK Dementia Research Institute, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - Pete A Williams
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Mark A Good
- School of Psychology, Cardiff University, Cardiff, UK
| | - B Paul Morgan
- UK Dementia Research Institute, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University, Cardiff, UK
| | - James E Morgan
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
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20
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Krukowski K, Nolan A, Frias ES, Boone M, Ureta G, Grue K, Paladini MS, Elizarraras E, Delgado L, Bernales S, Walter P, Rosi S. Small molecule cognitive enhancer reverses age-related memory decline in mice. eLife 2020; 9:e62048. [PMID: 33258451 PMCID: PMC7721440 DOI: 10.7554/elife.62048] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022] Open
Abstract
With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.
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Affiliation(s)
- Karen Krukowski
- Department of Physical Therapy and Rehabilitation Science, University of California at San FranciscoSan FranciscoUnited States
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
| | - Amber Nolan
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
- Department of Pathology, University of California at San FranciscoSan FranciscoUnited States
| | - Elma S Frias
- Department of Physical Therapy and Rehabilitation Science, University of California at San FranciscoSan FranciscoUnited States
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
| | - Morgane Boone
- Biochemistry and Biophysics, University of California at San FranciscoSan FranciscoUnited States
| | | | - Katherine Grue
- Department of Physical Therapy and Rehabilitation Science, University of California at San FranciscoSan FranciscoUnited States
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
| | - Maria-Serena Paladini
- Department of Physical Therapy and Rehabilitation Science, University of California at San FranciscoSan FranciscoUnited States
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
| | - Edward Elizarraras
- Department of Physical Therapy and Rehabilitation Science, University of California at San FranciscoSan FranciscoUnited States
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
| | | | | | - Peter Walter
- Biochemistry and Biophysics, University of California at San FranciscoSan FranciscoUnited States
- Howard Hughes Medical Institute, University of California at San FranciscoSan FranciscoUnited States
| | - Susanna Rosi
- Department of Physical Therapy and Rehabilitation Science, University of California at San FranciscoSan FranciscoUnited States
- Brain and Spinal Injury Center, University of California at San FranciscoSan FranciscoUnited States
- Department of Neurological Surgery, University of California at San FranciscoSan FranciscoUnited States
- Weill Institute for Neuroscience, University of California at San FranciscoSan FranciscoUnited States
- Kavli Institute of Fundamental Neuroscience, University of California at San FranciscoSan FranciscoUnited States
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21
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Pinto B, Morelli G, Rastogi M, Savardi A, Fumagalli A, Petretto A, Bartolucci M, Varea E, Catelani T, Contestabile A, Perlini LE, Cancedda L. Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome. Neuron 2020; 108:887-904.e12. [PMID: 33027640 PMCID: PMC7736620 DOI: 10.1016/j.neuron.2020.09.010] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 07/16/2020] [Accepted: 09/04/2020] [Indexed: 01/01/2023]
Abstract
Microglia are brain-resident immune cells and regulate mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by a supernumerary chromosome 21, containing also genes related to the immune system. In the hippocampus of the Dp(16) mouse model of DS and DS individuals, we found activated microglia, as assessed by their morphology; activation markers; and, for DS mice, electrophysiological profile. Accordingly, we found increased pro-inflammatory cytokine levels and altered interferon signaling in Dp(16) hippocampi. DS mice also showed decreased spine density and activity of hippocampal neurons and hippocampus-dependent cognitive behavioral deficits. Depletion of defective microglia or treatment with a commonly used anti-inflammatory drug rescued the neuronal spine and activity impairments and cognitive deficits in juvenile Dp(16) mice. Our results suggest an involvement of microglia in Dp(16)-mouse cognitive deficits and identify a new potential therapeutic approach for cognitive disabilities in DS individuals.
DS mice display microglia alterations and cognitive impairment Depletion of microglia rescues cognitive impairment in DS mice Acetaminophen treatment rescues microglia and cognitive impairments in DS mice Brain samples of DS people recapitulate microglia alterations observed in DS mice
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Affiliation(s)
- Bruno Pinto
- BIO@SNS, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126 Pisa, Italy; Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Giovanni Morelli
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Mohit Rastogi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Annalisa Savardi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Amos Fumagalli
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Andrea Petretto
- Core Facilities - Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Martina Bartolucci
- Core Facilities - Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Emilio Varea
- Cellular Biology Department, University of Valencia, Valencia, Spain
| | - Tiziano Catelani
- Electron Microscopy Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Andrea Contestabile
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Laura E Perlini
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Laura Cancedda
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy; Dulbecco Telethon Institute, Rome, Italy.
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22
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Zagrebelsky M, Tacke C, Korte M. BDNF signaling during the lifetime of dendritic spines. Cell Tissue Res 2020; 382:185-199. [PMID: 32537724 PMCID: PMC7529616 DOI: 10.1007/s00441-020-03226-5] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022]
Abstract
Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.
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Affiliation(s)
- Marta Zagrebelsky
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr 7, 38106, Braunschweig, Germany.
- Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, D-38124, Braunschweig, Germany.
| | - Charlotte Tacke
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr 7, 38106, Braunschweig, Germany
| | - Martin Korte
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr 7, 38106, Braunschweig, Germany.
- Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, D-38124, Braunschweig, Germany.
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23
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Ruíz-Salinas AK, Vázquez-Roque RA, Díaz A, Pulido G, Treviño S, Floran B, Flores G. The treatment of Goji berry (Lycium barbarum) improves the neuroplasticity of the prefrontal cortex and hippocampus in aged rats. J Nutr Biochem 2020; 83:108416. [PMID: 32554223 DOI: 10.1016/j.jnutbio.2020.108416] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 03/06/2020] [Accepted: 05/02/2020] [Indexed: 12/17/2022]
Abstract
The main characteristic of brain aging is an exacerbated inflammatory and oxidative response that affects dendritic morphology and the function of the neurons of the prefrontal cortex (PFC) and the hippocampus. This consequently causes memory loss. Recently, the use of the Goji berry (Lycium barbarum) as an antioxidant extract has provided neuroprotection and neuroplasticity, however, its therapeutic potential has not been demonstrated in aging conditions. The objective of this study was to evaluate the effect of Goji administration on memory recognition, as well as the changes in the dendritic morphology of the PFC and Hippocampus pyramidal neurons in old rats. Goji (3 g/kg) was administrated for 60 days in 18-month-old rats. After the treatment, recognition memory was evaluated using the new object recognition task (NORt). The changes in the neuron morphology of the PFC and hippocampus pyramidal neurons in old rats were evaluated by Golgi-cox stain and immunoreactivity for synaptophysin, glial fibrillary acidic protein (GFAP), caspase-3, 3-nitrotyrosine (3-NT) and nuclear factor erythroid 2-related factor 2 (Nrf2). The rats treated with Goji showed a significant increase in dendritic morphology in the PFC and hippocampus neurons, a greater immunoreactivity to synaptophysin and a decrease in reactive astrogliosis and also in caspase-3, in 3-NT and in Nrf2 in these brain regions was also observed. Goji administration promotes the plasticity processes in the PFC and in the hippocampus of old rats, critical structures in the brain aging process.
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Affiliation(s)
- Ana Karen Ruíz-Salinas
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, CP: 72570, Puebla, Mexico
| | - Rubén A Vázquez-Roque
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, CP: 72570, Puebla, Mexico
| | - Alfonso Díaz
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, CP: 72570, Puebla, Mexico
| | - Guadalupe Pulido
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, CP: 72570, Puebla, Mexico
| | - Samuel Treviño
- Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, CP: 72570, Puebla, Mexico
| | - Benjamín Floran
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigaciones y Estudios Avanzados IPN, DF, Mexico
| | - Gonzalo Flores
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, 14 Sur 6301, CP: 72570, Puebla, Mexico.
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24
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Jiménez-Rubio G, Herrera-Pérez JJ, Martínez-Becerril HA, Márquez-Baltazar MS, Martínez-Mota L. Age-dependent effects of testosterone on spatial memory in male rats. Horm Behav 2020; 122:104748. [PMID: 32222529 DOI: 10.1016/j.yhbeh.2020.104748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 03/20/2020] [Accepted: 03/22/2020] [Indexed: 11/21/2022]
Abstract
Decreased spatial memory is common in aging populations and reduces their quality of life. Although its role is still controversial, low testosterone (T) may contribute to impaired cognition in aged men. This study aimed to identify the role of T in age-related deficiencies in spatial memory among male rats. Young adult (3 months old) and aged (21 months old) Wistar rats were assigned to independent groups: intact, orchidectomized, or orchidectomized + subcutaneous pellets of T propionate. The phases of spatial memory acquisition (4 daily trials/4 days) and spatial memory retention (1 trial/day, 3 and 12 days after acquisition) were evaluated using the Barnes maze. Compared with young adults, aged intact rats took longer to find the goal, made more mistakes, and showed only slight improvements in goal sector exploration across the acquisition period. The young orchidectomized rats showed no improvement in performance over the days during the acquisition phase. T treatment in hormonally deprived old rats produced a small improvement in goal sector exploration and number of errors during the acquisition phase. Meanwhile, in young adults, this treatment improved the goal sector searching in the retention phase (12 days after acquisition training). Our results suggested that age-related spatial memory deficits cannot be entirely explained by the decline in T levels; however, this androgen produced subtle and mild beneficial effects on spatial memory in young and old males. Taken together, our findings suggest age differences in the role of T on spatial memory in males.
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Affiliation(s)
- Graciela Jiménez-Rubio
- Laboratorio de Farmacología Conductual, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, 14370 Ciudad de México, Mexico
| | - José Jaime Herrera-Pérez
- Laboratorio de Farmacología Conductual, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, 14370 Ciudad de México, Mexico
| | - Hilda Angélica Martínez-Becerril
- Laboratorio de Farmacología Conductual, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, 14370 Ciudad de México, Mexico
| | - Martín Sergio Márquez-Baltazar
- Laboratorio de Farmacología Conductual, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, 14370 Ciudad de México, Mexico
| | - Lucía Martínez-Mota
- Laboratorio de Farmacología Conductual, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, 14370 Ciudad de México, Mexico.
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25
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Hrynchak MV, Rierola M, Golovyashkina N, Penazzi L, Pump WC, David B, Sündermann F, Brandt R, Bakota L. Chronic Presence of Oligomeric Aβ Differentially Modulates Spine Parameters in the Hippocampus and Cortex of Mice With Low APP Transgene Expression. Front Synaptic Neurosci 2020; 12:16. [PMID: 32390822 PMCID: PMC7194154 DOI: 10.3389/fnsyn.2020.00016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/25/2020] [Indexed: 01/06/2023] Open
Abstract
Alzheimer’s disease is regarded as a synaptopathy with a long presymptomatic phase. Soluble, oligomeric amyloid-β (Aβ) is thought to play a causative role in this disease, which eventually leads to cognitive decline. However, most animal studies have employed mice expressing high levels of the Aβ precursor protein (APP) transgene to drive pathology. Here, to understand how the principal neurons in different brain regions cope with moderate, chronically present levels of Aβ, we employed transgenic mice expressing equal levels of mouse and human APP carrying a combination of three familial AD (FAD)-linked mutations (Swedish, Dutch, and London), that develop plaques only in old age. We analyzed dendritic spine parameters in hippocampal and cortical brain regions after targeted expression of EGFP to allow high-resolution imaging, followed by algorithm-based evaluation of mice of both sexes from adolescence to old age. We report that Aβ species gradually accumulated throughout the life of APPSDL mice, but not the oligomeric forms, and that the amount of membrane-associated oligomers decreased at the onset of plaque formation. We observed an age-dependent loss of thin spines under most conditions as an indicator of a loss of synaptic plasticity in older mice. We further found that hippocampal pyramidal neurons respond to increased Aβ levels by lowering spine density and shifting spine morphology, which reached significance in the CA1 subfield. In contrast, the spine density in cortical pyramidal neurons of APPSDL mice was unchanged. We also observed an increase in the protein levels of PSD-95 and Arc in the hippocampus and cortex, respectively. Our data demonstrated that increased concentrations of Aβ have diverse effects on dendritic spines in the brain and suggest that hippocampal and cortical neurons have different adaptive and compensatory capacity during their lifetime. Our data also indicated that spine morphology differs between sexes in a region-specific manner.
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Affiliation(s)
- Mariya V Hrynchak
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Marina Rierola
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Nataliya Golovyashkina
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Lorène Penazzi
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Wiebke C Pump
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Bastian David
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Frederik Sündermann
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
| | - Roland Brandt
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany.,Center for Cellular Nanoanalytics, University of Osnabrück, Osnabrück, Germany.,Institute of Cognitive Science, University of Osnabrück, Osnabrück, Germany
| | - Lidia Bakota
- Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany
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26
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Restored presynaptic synaptophysin and cholinergic inputs contribute to the protective effects of physical running on spatial memory in aged mice. Neurobiol Dis 2019; 132:104586. [DOI: 10.1016/j.nbd.2019.104586] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 08/06/2019] [Accepted: 08/23/2019] [Indexed: 01/16/2023] Open
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27
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Vo HT, Phillips ML, Herskowitz JH, King GD. Klotho deficiency affects the spine morphology and network synchronization of neurons. Mol Cell Neurosci 2019; 98:1-11. [PMID: 30991103 PMCID: PMC6613977 DOI: 10.1016/j.mcn.2019.04.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/25/2019] [Accepted: 04/09/2019] [Indexed: 01/01/2023] Open
Abstract
Klotho-deficient mice rapidly develop cognitive impairment and show some evidence of the onset of neurodegeneration. However, it is impossible to investigate the long-term consequences on the brain because of the dramatic shortening of lifespan caused by systemic klotho deficiency. As klotho expression is downregulated with advancing organismal age, understanding the mechanisms of klotho action is important for developing novel strategies to support healthy brain aging. Previously, we reported that klotho-deficient mice show enhanced long-term potentiation prior to the onset of cognitive impairment. To inform this unusual phenotype, herein, we examined neuronal structure and in vitro synaptic function. Our results indicate that klotho deficiency causes the population of dendritic spines to shift towards increased head diameter and decreased length consistent with mature, mushroom type spines. Multi-electrode array recordings from klotho-deficient neurons show increased synchronous firing and activity changes reflective of increased neuronal network activity. Supplementation of the neuronal growth media with recombinant shed klotho corrected some but not all of the activity changes caused by klotho deficiency. Last, in vivo we found that klotho-deficient mice have a decreased latency to induced seizure activity. Together these data show that klotho-deficient memory impairments are underpinned by structural and functional changes that may preclude ongoing normal cognition.
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Affiliation(s)
- Hai T Vo
- Department of Neurobiology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 913, Birmingham 35294, AL, USA
| | - Mary L Phillips
- Department of Neurobiology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 913, Birmingham 35294, AL, USA
| | - Jeremy H Herskowitz
- Department of Neurology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 1114, Birmingham 35294, AL, USA
| | - Gwendalyn D King
- Department of Neurobiology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 913, Birmingham 35294, AL, USA.
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28
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Flores‐Vivaldo YM, Camacho‐Abrego I, Picazo O, Flores G. Pregnancies alters spine number in cortical and subcortical limbic brain regions of old rats. Synapse 2019; 73:e22100. [DOI: 10.1002/syn.22100] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 04/03/2019] [Accepted: 04/04/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Yaredit Margarita Flores‐Vivaldo
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología Benemérita Universidad Autónoma de Puebla Puebla Mexico
- Escuela Superior de Medicina, Instituto Politécnico Nacional Mexico City Mexico
| | - Israel Camacho‐Abrego
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología Benemérita Universidad Autónoma de Puebla Puebla Mexico
| | - Ofir Picazo
- Escuela Superior de Medicina, Instituto Politécnico Nacional Mexico City Mexico
| | - Gonzalo Flores
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología Benemérita Universidad Autónoma de Puebla Puebla Mexico
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29
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Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion. Neural Plast 2019; 2019:2158285. [PMID: 30923551 PMCID: PMC6409048 DOI: 10.1155/2019/2158285] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/10/2018] [Accepted: 12/16/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.
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