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Targeting synaptic pathology in Alzheimer’s disease

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Zoological Research 2024年第4期45卷 875-876页

作者： Jing Cao yun-wu zhang Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of NeuroscienceSchool of MedicineXiamen UniversityXiamenFujian 361102China

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by memory and cognitive *** two primary pathological hallmarks of AD include the accumulation ofβ-amyloid(Aβ)plaques and formation of neurofibrillary tangles(NFTs)composed predominantly of hyperphosphorylated tau protein(zhang et al.,2023).Moreover,synaptic dysfunction is considered another crucial factor in AD pathogenesis and is closely associated with cognitive ***,synaptic damage,loss,and dysfunction manifest earlier than the pathological features of Aβplaques and NFTs(Knopman et al.,2021).Therefore,understanding the mechanisms underlying synaptic dysfunction in AD is vital for providing insights into disease mechanisms and developing novel therapeutic strategies.

关键词： Alzheimer Aβ tau

Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease

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Zoological Research 2023年第5期44卷 867-881页

作者： Ting Wang yun-Qiang Zhou Yong Wang Liang zhang Xiang Zhu Xiu-Yan Wang Jing-Hui Wang Lin-Kun Han Jian Meng Xian zhang Hong Luo Qi-Lin Ma Zhan-Xiang Wang yun-wu zhang Xiamen Key Laboratory of Brain Center The First Affiliated Hospital of Xiamen Universityand Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging ResearchInstitute of NeuroscienceSchool of MedicineXiamen UniversityXiamenFujian 361102China Fujian Provincial Clinical Research Center for Brain Diseases The First Affiliated Hospital of Xiamen UniversityXiamenFujian 361003China

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease(AD).High-frequency stimulation(HFS)-induced long-term potentiation(LTP)has been widely used to study synaptic plasticity,with impaired LTP found to be associated with ***,the exact molecular mechanism underlying synaptic plasticity has yet to be completely *** genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains ***,we induced LTP in the hippocampal CA1 region of wildtype(WT)and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 *** identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes(DEGs)in mice with normal LTP,and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired *** further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS *** them,we found that the expression of Pygm,which catabolizes glycogen,was also decreased in AD *** further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice,while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD ***,we showed that PYGM directly regulated energy generation in *** study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function,but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.

关键词： Alzheimer's disease High-frequency stimulation Long-term potentiation PYGM Synaptic plasticity Transcriptome

SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate

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National Science Review 2021年第7期8卷 72-85页

作者： Hongfeng zhang Yujuan Hong Weijie Yang Ruimin Wang Ting Yao Jian Wang Ke Liu Huilong Yuan Chaoqun Xu Yuanyuan Zhou Guanxian Li Lishan zhang Hong Luo Xian zhang Dan Du Hao Sun Qiuyang Zheng yun-wu zhang Yingjun Zhao Ying Zhou Huaxi Xu Xin Wang State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience School of Medicine Xiamen University National Institute for Data Science in Health and Medicine School of Medicine Xiamen University Cancer Research Center Department of Stomatology School of Medicine Xiamen University

Loss-of-function mutations in sorting nexin 14(SNX14) cause autosomal recessive spinocerebellar ataxia20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of highenergy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggested valproate as a potential therapeutic agent.

关键词： sorting nexin 14 cerebellar ataxia Purkinje cell degeneration mitochondrial dysfunction axonal transport valproate

Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer＇s Disease

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Chinese Medical Journal 2017年第24期130卷 2978-2990页

作者： Xi-Lin wu Juan Pina-Crespo yun-wu zhang Xiao-Chun Chen Hua-Xi Xu Neuroscience Initiative Neuroscience and Aging Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA 92037 USA Department of Neurology Fujian Institute of Geriatrics Fujian Medical University Union Hospital Fujian Key Laboratory of Molecular Neurology Fujian Medical University Fuzhou Fujian 350001 China Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience College of Medicine Xiamen University XiamenFujian 361102 China

Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD *** Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google *** Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational *** articles were carefully reviewed,with no exclusions applied to study design and publication ***：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks *** the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD *** research focus in AD has recently shifted to the role oftau in *** addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological *** evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD *** to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the *** advances have potential to accurately determine tau levels at early diagnostic stages in *** that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD ***：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.

关键词： Alzheimer's Disease Biomarker lmmunotherapy Tau Imaging Tau Protein Transcellular Propagation

APOE interacts with ACE2 inhibitingg SARS-CoV-2 cellular entry and inflammation in COVID-19 patients

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3459-3467页

作者： Hongsheng zhang Lin Shao Zhihao Lin Quan-Xin Long Huilong Yuan Lujian Cai Guangtong Jiang Xiaoyi Guo Renzhi Yang Zepeng zhang Bingchang zhang Fan Liu Zhiyong Li Qilin Ma yun-wu zhang Ai-Long Huang Zhanxiang Wang Yingjun Zhao Huaxi Xu Center for Brain Sciences the First Aliated Hospital of Xiamen UniversityInstitute of NeuroscienceFujian Provincial Key Laboratory of Neurodegenerative Disease and Aging ResearchXiamen UniversityXiamenChina Institute for Brain Science and Disease Chongqing Medical UniversityChongqingChina school of Medicine Xiamen UniversityXiamenChina Key Laboratory of Molecular Biology for Infectius Diseases(Minstry of Educatio) Chongqing Medical UniversityChongqingChina

Apolipoprotein E(APOE)plays a pivotal role in lipid including cholesterol *** APOE 4(APOE4)allele is a major genetic risk factor for Alzheimer's and cardiovascular *** APOE has recently been associated with increased susceptibility to infections of several viruses,whether and how APOEand its isoforms affect SARS-CoV-2 infection remains ***,we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 *** multiple protein interaction assays,we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2;and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2,a key docking site for SARS-CoV-2 Spike *** addition,immuno-imaging assays using confocal,super-resolution,and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spikemediated viral entry into ***,while having a comparable binding affinity to ACE2,APOE4 inhibits viral entry to a lesser extent compared to APOE3,which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ***,APOE e4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients *** study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2,which may explain in part increased COVID-19 infection and disease severity in APOE e4 carriers.

关键词： ACE2 patients inflammation

M1 muscarinic acetylcholine receptor in Alzheimer's disease

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Neuroscience Bulletin 2014年第2期30卷 295-307页

作者： Shangtong Jiang Yanfang Li Cuilin zhang Yingjun Zhao Guojun Bu Huaxi Xu yun-wu zhang Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience College of Medicine Xiamen University School of Pharmaceutical Sciences Xiamen University Degenerative Disease Research Program Sanford-Burnham Medical Research Institute

The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer＇s disease （AD）. Muscarinic acetylcholine receptors （mAChRs） mediate acetylcholine-induced neurotransmission and five mAChR subtypes （M1-M5） have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists forAD treatment.

关键词： agonist Alzheimer's disease amyloid cholinergic hypofunction M1 muscarinic acetylcholinereceptor tau

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主从编队反舰导弹末制导段一体化位姿控制

宇航学报 2016年第12期37卷 1441-1448页

作者：吴云洁张聪北京航空航天大学虚拟现实技术与系统国家重点实验室北京100191 北京航空航天大学自动化科学与电气工程学院北京100191 北京航空航天大学飞行器控制一体化技术重点实验室北京100191

针对领弹—从弹编队构型的反舰导弹的末段协同制导,提出一体化位姿控制(ICPA)策略,将传统的位置跟踪控制和姿态稳定控制集成一体。建立便于一体化策略实施的串级型设计模型,在动态面控制的框架下设计一体化位姿控制算法,并通过Lyapunov... 详细信息

针对领弹—从弹编队构型的反舰导弹的末段协同制导,提出一体化位姿控制(ICPA)策略,将传统的位置跟踪控制和姿态稳定控制集成一体。建立便于一体化策略实施的串级型设计模型,在动态面控制的框架下设计一体化位姿控制算法,并通过Lyapunov方法证明其稳定性。从弹仅需获取领弹的位置信息,就能在确保自身姿态稳定的同时精确跟踪期望位置保持编队构型,而无需领弹的航向、速度、姿态等其他信息。总结一体化设计思想的本质:通过一个中间状态量建立质心方程和姿态方程之间的直接联系,集成出一个串级型设计模型,并针对其进行闭环算法设计。最后,通过仿真对所提出的一体化位姿控制策略及算法进行校验。

关键词：反舰导弹一体化位姿控制主从编队末制导段动态面控制

High Temperature Deformation of Al_2O_3/Cu Composites

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Journal of Materials Science & Technology 2001年第3期17卷 325-328页

作者： Jianjun wu. yun zhang, Yanfei JIANG and Meiyun XUE Department of Material Science and Engineering, Hebei University of Technology, Tianjin 300130, China Tingquan LEI School of Materials Science and Engineering, Harbin Institute of Technology, Uarbin 15000 Hebei Univ Technol Dept Mat Sci & Engn Tianjin 300130 Peoples R China Harbin Inst Technol Sch Mat Sci & Engn Harbin 150006 Peoples R China

This work concerns with the high temperature deformation of internally oxidized Al2O3/Cu composites. The investigation revealed that dispersive alumina can obstruct dislocation sliding and define the subgrain size thereby improve significantly the strength of the materials at high temperature. The sliding of dislocations is a main deformation mechanism in the given temperature range. The sliding of grain boundary and diffusive creep play important roles at high temperature and low strain rate. The dispersoids can raise the recrystallization temperature to higher than 1223 K. Dynamic recovery is a main softening way under the experimental conditions. Higher deformation rate and lower deformation temperature imply a higher flow stress.

关键词： High Temperature Deformation of Al2O3/Cu Composites Cu Al

Sex-dependent alterations in extracellular vesicles linking chronic spinal cord injury to brain neuroinflammation and neurodegeneration

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Neural Regeneration Research 2025年第2期20卷 483-484页

作者： yun Li Junfang wu Department of Anesthesiology&Shock Trauma and Anesthesiology Research(STAR)CenterUniversity of Maryland School of MedicineBaltimoreMDUSA

Traumatic spinal cord injury(SCI)is a devastating exogenous injury with long-lasting consequences and a leading cause of death and disability *** in assistive technology,rehabilitative interventions,and the ability to identify and intervene in secondary conditions have significantly increased the long-term survival rate of SCI patients,with some people even living well into their seventh or eighth *** survival changes have led neurotrauma researchers to examine how SCI interacts with brain *** health and epidemiological data showed that patients with long-term SCI can have a lower life expectancy and quality of life,along with a higher risk of comorbidities and complications.

关键词： alterations inflammation injury