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Apolipoprotein E in Alzheimer's Disease: Focus on synaptic function and Therapeutic Strategy

MOLECULAR NEUROBIOLOGY 2025年第3期62卷 3040-3052页

作者： Qu, Longjie Xu, Shuai Lan, Zhen Fang, Shuang Xu, Yun Zhu, Xiaolei Nanjing Med Univ Nanjing Drum Tower Hosp Dept Neurol Clin Coll Nanjing 210008 Peoples R China Nanjing Univ Nanjing Drum Tower Hosp Affiliated Hosp Dept NeurolMed Sch Nanjing 210008 Peoples R China Nanjing Univ State Key Lab Pharmaceut Biotechnol Nanjing 210008 Peoples R China Nanjing Univ Inst Translat Med Brain Crit Dis Nanjing 210008 Peoples R China Nanjing Univ Jiangsu Key Lab Mol Med Med Sch Nanjing 210008 Peoples R China Nanjing Neurol Clin Med Ctr Nanjing 210008 Peoples R China

synaptic dysfunction is a critical pathological feature in the early phase of Alzheimer's disease (AD) that precedes typical hallmarks of AD, including beta-amyloid (A beta) plaques and neurofibrillary tangles. However, the underlying mechanism of synaptic dysfunction remains incompletely defined. Apolipoprotein E (APOE) has been shown to play a key role in the pathogenesis of AD, and the epsilon 4 allele of APOE remains the strongest genetic risk factor for sporadic AD. It is widely recognized that APOE4 accelerates the development of A beta and tau pathology in AD. Recent studies have indicated that APOE affects synaptic function through a variety of pathways. Here, we summarize the mechanism of modulating synapses by various APOE isoforms and demonstrate the therapeutic potential by targeting APOE4 for AD treatment.

关键词： Alzheimer's disease Apolipoprotein E synaptic function

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Deciphering the Role of Shank3 in Dendritic Morphology and synaptic function Across Postnatal Developmental Stages in the Shank3B KO Mouse

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NEUROSCIENCE BULLETIN 2025年第4期41卷 583-599页

作者： Yang, Jing Ma, Guaiguai Du, Xiaohui Xie, Jinyi Wang, Mengmeng Wang, Wenting Guo, Baolin Wu, Shengxi Hangzhou City Univ Sch Med Dept Basic Med Hangzhou 310015 Peoples R China Fourth Mil Med Univ Sch Basic Med Dept Neurobiol Xian 710032 Peoples R China Fourth Mil Med Univ Xijing Hosp Innovat Res Inst Xian 710032 Peoples R China

Autism Spectrum Disorder (ASD) is marked by early-onset neurodevelopmental anomalies, yet the temporal dynamics of genetic contributions to these processes remain insufficiently understood. This study aimed to elucidate the role of the Shank3 gene, known to be associated with monogenic causes of autism, in early developmental processes to inform the timing and mechanisms for potential interventions for ASD. Utilizing the Shank3B knockout (KO) mouse model, we examined Shank3 expression and its impact on neuronal maturation through Golgi staining for dendritic morphology and electrophysiological recordings to measure synaptic function in the anterior cingulate cortex (ACC) across different postnatal stages. Our longitudinal analysis revealed that, while Shank3B KO mice displayed normal neuronal morphology at one week postnatal, significant impairments in dendritic growth and synaptic activity emerged by two to three weeks. These findings highlight the critical developmental window during which Shank3 is essential for neuronal and synaptic maturation in the ACC.

关键词： Autism Shank3 Neuronal development Dendritic development synaptic function

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Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease

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BIOMATERIALS 2025年 318卷 123142-123142页

作者： Park, Elliya He, Chunsheng Abbasi, Azhar Z. Tian, Meng Huang, Shudi Wang, Liting Georgiou, John Collingridge, Graham L. Fraser, Paul E. Henderson, Jeffrey T. Wu, Xiao Yu Univ Toronto Leslie Dan Fac Pharm 144 Coll St Toronto ON M5S 3M2 Canada Univ Toronto Tanz Ctr Res Neurodegenerat Dis 135 Nassau St Toronto ON M5T 1M8 Canada Mt Sinai Hosp Lunenfeld Tanenbaum Res Inst 600 Univ Ave Toronto ON M5G 1X5 Canada Univ Toronto Tanz Ctr Res Neurodegenerat Dis Dept Med Biophys 60 Leonard Ave Toronto ON M5T 2S8 Canada

The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated. To examine this, a transgenic mouse model of Alzheimer's disease (TgCRND8) in vivo were treated intravenously with beta-amyloid antibody-conjugated (Ab), blood-brain barrier- crossing terpolymer (TP) containing polymer-lipid based manganese dioxide nanoparticles (Ab-TP-MDNPs). Alterations in cerebral glucose utilization were determined by [18F]FDG-PET imaging in vivo, with glucose metabolism and mitochondrial activity analyzed by biomarkers and studies with primary neurons in vitro. synaptic function was evaluated by both biomarkers and electrophysiologic analysis. Current study shows that intravenously administered Ab-TP-MDNPs enhanced cerebral glucose utilization, improved glucose metabolism, mitochondrial activity, and increased the levels of neprilysin, O-glycosylation. The consequence of this was enhanced glucose and ATP availability, resulting in improved long-term potentiation for promoting neuronal synaptic function. This study highlights the importance of targeting the metabolism of complex disease pathologies in addressing disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease.

关键词： Blood brain barrier-crossing nanomedicine Biocompatible hybrid manganese dioxide nanoparticles Disease-modifying treatment of Alzheimer's disease Glucose metabolism Glucose utilization Mitochondrial function synaptic function

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Muscone enhances synaptic function in vascular dementia through activating BDNF-TrkB-NP2 signaling pathway

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INTERNATIONAL IMMUNOPHARMACOLOGY 2025年 149卷 114232页

作者： Huang, Ping Sun, Hao Chen, Yuang Li, Jiacheng Peng, Yuqin Ge, Chaowen Zhu, Kai Zhou, Xian Chang, Dennis Wang, Ning Anhui Univ Chinese Med Anhui Prov Key Lab Chinese Med Formula Hefei 230012 Anhui Peoples R China Anhui Acad Chinese Med Inst Pharmacodynam & Safety Evaluat Chinese Med Hefei 230012 Anhui Peoples R China Anhui Acad Chinese Med Lab Geriatr Care & Hlth Hefei 230012 Anhui Peoples R China Western Sydney Univ Natl Inst Complementary Med Westmead NSW 2145 Australia

Objective: The objective of this study is to explore the mechanism by which Muscone treats VD. Methods: Cognitive function was evaluated by behavioral tests, cerebral blood flow(CBF) was detected with laser speckle imaging(LSI) on rat model induced by bilateral common carotid artery ligation(2-VO). To further elucidate the mechanism of Muscone acts on synaptic function, Mendelian randomization test was employed to identify neuronal pentraxin receptor (NPTXR) as a risk factor for VD. Subsequently, Oxygen and GlucoseDeprivation/Reoxygenation (OGD/R) model was established in HT22 cells. BDNF transfection, protein docking, and co-immunoprecipitation were utilized to validate whether the protective effect of Muscone is mediated through regulation of the BDNF-TrkB-NP2 pathway. Results: Muscone significantly enhanced the cognitive performance, memory capacity in rats, promoted axonal growth and increased dendritic spine density. Muscone effectively improved cell survival rates, mitigated the accumulation of ROS and Ca2+ following OGD/R treatment. Furthermore, Muscone led to a significant upregulation of synapse-associated proteins expression. Importantly, Muscone exhibited a notable ability to elevate BDNF levels, with subsequent binding with its downstream molecule TrkB to NP2. Conclusion: The activation of the BDNF-TrkB-NP2 pathway and synaptic function enhancement by Muscone contribute to its protective effect against VD injury. Therefore, our study uncovers a novel mechanism underlying the anti-VD properties of Muscone.

关键词： Muscone BDNF-TrkB-NP2 Mendelian randomization synaptic function Vascular dementia (VD) Oxygen Glucose-deprivation/reoxygenation (OGD/R)

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CRMP2 in the hippocampus alleviates chronic stress-induced depressive-like behaviours in mice by affecting synaptic function

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BEHAVIOURAL BRAIN RESEARCH 2025年 484卷 115495页

作者： Li, Ruiling Zhang, Yuhui Zhang, Honghan Wang, Chao Duan, Hao Sun, Siqi Xiang, Dan Liu, Zhongchun Wuhan Univ Renmin Hosp Dept Psychiat 99 Jiefang Rd Wuhan 430060 Hubei Peoples R China Wuhan Univ TaiKang Ctr Life & Med Sci Wuhan Peoples R China

Major depressive disorder (MDD) is a prevalent psychiatric illness and a significant contributor to the global burden of disease. However, the molecular mechanisms underlying depression are complex and have yet to be fully elucidated. Previous studies demonstrated that collapsin response mediator protein 2 (CRMP2) involved in the onset of depression, but its role is unclear yet. To explore the mechanism of CRMP2 in depression and whether it ameliorates depressive-like behaviours by modulating synaptic functions, we manipulate the expression of CRMP2 by adeno-associated virus (AAV) injected into the hippocampal CA1 region and then induced depressive-like behaviour by subjecting the mice to chronic unpredictable mild stress (CUMS). Sucrose preference test (SPT), open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) are utilized to detect behavioral changes. Golgi-Cox staining and electron microscopy were applied to examine alterations in the structure and morphology of neural synapses. Synaptophysin (SYP), synaptophysin 1 (SYN1), growth-associated protein 43 (GAP43), glutamate receptor 2 (GLUR2) and postsynaptic density protein 95 (PSD95) is tested for synaptic function. The proteins interacting with CRMP2 were comprehensively investigated utilizing Immunoprecipitation-Mass Spectrometry (IP-MS) analysis and the direct binding between CRMP2 and PSD95 was validated. In our study, we observed CRMP2 in the hippocampal CA1 region was downregulated following CUMS. Knockdown of CRMP2 resulted in impaired synaptic structure and decreased expression of synapse-associated proteins, accompanied by increased depressive-like behaviour, like anhedonia and hopelessness. Conversely, overexpression of CRMP2 significantly ameliorated behavioural deficits associated with depression and restore the compromised synaptic structure and function. Our findings suggest that CRMP2 exerts a crucial function in modulating depressive-like

关键词： Collapsin response mediator protein 2 Major depressive disorder synaptic function PSD95

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Electrophysiological properties and synaptic function of mesenchymal stem cells during neurogenic differentiation - a mini-review

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INTERNATIONAL JOURNAL OF ARTIFICIAL ORGANS 2012年第5期35卷 323-337页

作者： Liu, Jing Song, Lin Jiang, Changbin Liu, Yang George, Julian Ye, Hue Cui, Zhanfeng Univ Oxford Dept Engn Sci Inst Biomed Engn Oxford OX1 2JD England Dalian Med Univ Affiliated Hosp 1 Ctr Regenerat Med Dalian Peoples R China Dalian Univ Technol Sch Life Sci & Biotechnol Dalian Peoples R China Dalian Med Univ Affiliated Hosp 1 Dept Neurol Dalian Peoples R China

Introduction: Mesenchymal stem cells (MSCs) have gained considerable interest due to their potential use in cell therapies and tissue engineering. They have been reported to differentiate into various anchorage-dependent cell types, including bone, cartilage, and tendon. Our focus is on the differentiation of MSCs into neuron-like cells through the use of soluble chemical stimuli or specific growth factor supplements. The resulting cells appear to adopt neural phenotypes and express some typical neuronal markers, however, their electrophysiological properties and synaptic function remains unclear. Results: This mini-review illustrates how particular characteristics, electrophysiological properties, and synaptic functions of MSCs change during their neuronal differentiation. In particular we focus on changes in ion currents, ion channels, synaptic communication, and neurotransmitter release. We also highlight conflicting results, caused by inconsistencies in the experimental conditions used and in the methodologies adopted. Conclusions: We conclude that there is insufficient data and that further, carefully controlled investigations are required in order to ascertain whether MSC-derived neuron-like cells can exhibit the necessary neuronal functions to become clinically relevant for use in neural repairs.

关键词： Mesenchymal stem cells Electrophysiological properties synaptic function Neuronal differentiation Review

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Extra virgin olive oil beneficial effects on memory, synaptic function, and neuroinflammation in a mouse model of Down syndrome

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JOURNAL OF ALZHEIMERS DISEASE 2024年第1期102卷 35-43页

作者： Li, Jian-Guo Leone, Alessandro Servili, Maurizio Pratico, Domenico Temple Univ Lewis Katz Sch Med Dept Neural Sci 3500 North Broad StMERBsuite 660 Philadelphia PA 19140 USA Univ Bari Aldo Moro Dept Soil Plant & Food Sci DISSPA Bari Italy Univ Perugia Dept Agr Food & Environm Sci Perugia Italy

Background: Clinical and preclinical studies have shown that extra virgin olive oil (EVOO), a major component of the Mediterranean diet, has beneficial effects on brain aging and cognition. Individuals with Down syndrome develop age-dependent cognitive decline and synaptic dysfunction. However, whether EVOO intake is beneficial in Down syndrome is not known. Objective: In this study, by implementing a mouse model of Down syndrome, we aimed to investigate the effect that chronic administration of EVOO has on memory, synaptic function, and neuroinflammation. Methods: Starting at 4 months of age Ts65dn mice were randomized to receive EVOO for 5 months in their diet, after which they were tested for learning and memory impairment. After euthanasia, synaptic function was measured in freshly obtained hippocampal slices, whereas brain tissues were assessed for inflammatory biomarkers. Results: Compared with controls, mice receiving EVOO had a significant improvement in learning and spatial memory. Additionally, field potential recordings showed that treated mice had an improvement in synaptic function. Finally, array analysis showed that EVOO modulated the expression levels of several inflammatory biomarkers. Conclusions: Chronic administration of EVOO to a mouse model of Down syndrome has beneficial effects on memory impairments, synaptic function deficits and neuroinflammation. Our findings provide additional support for the potential therapeutic effects of EVOO also in individuals with Down syndrome.

关键词： Alzheimer's disease animal model Down syndrome extra virgin olive oil memory deficits synaptic function

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In vivo tau pathology is associated with synaptic loss and altered synaptic function

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ALZHEIMERS RESEARCH & THERAPY 2021年第1期13卷 1-13页

作者： Coomans, Emma M. Schoonhoven, Deborah N. Tuncel, Hayel Verfaillie, Sander C. J. Wolters, Emma E. Boellaard, Ronald Ossenkoppele, Rik den Braber, Anouk Scheper, Wiep Schober, Patrick Sweeney, Steven P. Ryan, J. Michael Schuit, Robert C. Windhorst, Albert D. Barkhof, Frederik Scheltens, Philip Golla, Sandeep S., V Hillebrand, Arjan Gouw, Alida A. van Berckel, Bart N. M. Vrije Univ Amsterdam Dept Radiol & Nucl Med Amsterdam UMC Amsterdam Neurosci Amsterdam Netherlands Vrije Univ Amsterdam Alzheimer Ctr Amsterdam Dept Neurol Amsterdam NeurosciAmsterdam UMC Amsterdam Netherlands Vrije Univ Amsterdam Dept Clin Neurophysiol Amsterdam Neurosci Amsterdam UMC Amsterdam Netherlands Vrije Univ Amsterdam MEG Ctr Dept Neurol Amsterdam NeurosciAmsterdam UMC Amsterdam Netherlands Lund Univ Clin Memory Res Unit Lund Sweden Amsterdam UMC Dept Clin Genet Amsterdam Neurosci Amsterdam Netherlands Vrije Univ Fac Sci Ctr Neurogen & Cognit Res Dept Funct Genom Amsterdam Netherlands Vrije Univ Amsterdam Dept Anaesthesiol Amsterdam UMC Amsterdam Netherlands Rodin Therapeut Inc Cambridge MA USA UCL Inst Neurol & Healthcare Engn London England

Background The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([F-18]flortaucipir PET), synaptic density (synaptic vesicle 2A [C-11]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease. Methods Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [F-18]flortaucipir PET, dynamic 60-min [C-11]UCB-J PET with arterial sampling and 2 x 5-min resting-state MEG measurement. [F-18]flortaucipir- and [C-11]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power;broadband power;and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [F-18]flortaucipir BPND, [C-11]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. Results Across subjects, higher regional [F-18]flortaucipir uptake was associated with lower [C-11]UCB-J uptake. Within subjects, the association between [C-11]UCB-J and [F-18]flortaucipir depended on within-subject neocortical tau load;negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [F-18]flortaucipir and lower [C-11]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. Conclusions These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

关键词： Alzheimer Tau synaptic density synaptic function PET MEG

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GHS-R1a activity suppresses synaptic function of primary cultured hippocampal neurons

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2022年 602卷 91-97页

作者： Du, Anqi Li, Na Li, Zhilu Shen, Ruowu Li, Nan Zhou, Yu Qingdao Univ Sch Basic Med Sci Dept Physiol & Pathophysiol Qingdao 266071 Shandong Peoples R China Qingdao Univ Sch Basic Med Sci Dept Anat Qingdao 266071 Shandong Peoples R China Qingdao Binhai Univ Qingdao 266555 Shandong Peoples R China Qingdao Univ Dept Rehabil Med Affiliated Hosp Qingdao 266000 Shangdong Peoples R China Qingdao Univ Inst Brain Sci & Related Disorders Qingdao 266071 Shandong Peoples R China

Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulates energy homeostasis in both humans and rodents. Studies have reported intriguing yet conflicting roles that ghrelin and its receptor growth hormone secretagogue receptor 1a (GHS-R1a) play in regulating multiple brain functions, such as learning and memory;however, the underlying mechanism is largely unknown. In this study, we investigated the effect of ghrelin incubation and virus-mediated GHS-R1a overexpression on synaptic functions of primary cultured hippocampal neurons. Our results demonstrated that ghrelin pretreatment for 24 h, with a concentration of either 4 nM or 200 nM, suppressed the frequency of miniature excitatory postsynaptic currents (mEPSCs), the frequency and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Similarly, GHS-R1a overexpression inhibited both the frequency and the amplitude of mEPSCs, and mIPSCs frequency. Moreover, our in vitro Ca2+-image study with Rhod-3AM reveals that ghrelin pre-treatment for either 3 h or 24 h suppressed glutamate-induced elevation of cytoplasmic [Ca2+]. Our findings thus suggest that GHS-R1a signaling inhibits synaptic function of hippocampal neurons, which may contribute to the blocking effect of ghrelin on memory formation. (C) 2022 Elsevier Inc. All rights reserved.

关键词： Ghrelin GHS-R1a synaptic function Hippocampus Cultured neurons In vitro

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TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores synaptic function in CK-p25Tg Mice

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JOURNAL OF ALZHEIMERS DISEASE 2017年第1期56卷 335-349页

作者： Shukla, Varsha Seo, Jinsoo Binukumar, B. K. Amin, Niranjana D. Reddy, Preethi Grant, Philip Kuntz, Susan Kesavapany, Sashi Steiner, Joseph Mishra, Santosh K. Tsai, Li-Huei Pant, Harish C. NINDS NIH Bethesda MD 20892 USA MIT Picower Inst Learning & Memory Dept Brain & Cognit Sci Cambridge MA 02139 USA Natl Univ Singapore Singapore Singapore Natl Inst Dent & Craniofacial Res NIH Bethesda MA USA

It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-beta plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques;hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.

关键词： Alzheimer's disease cyclin-dependent kinase 5 hyperphosphorylation synaptic function TFP5

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