Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice

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外文摘要：Sporadic or late-onset Alzheimer's disease(LOAD)accounts for more than 95％of Alzheimer's disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of dementia.However,the underlying mechanisms of social isolation in AD progression remain elusive.In the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice.We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultane-ously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related pro-teins.Interestingly,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious cycle.Finally,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its partners.Moreover,application of senktide in vivo effec-tively restored DG circuit disorders in socially isolated AD mice.Taken together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

外文关键词：

Alzheimer's diseasememory impairmentsynaptic disordertau pathology

作者：

He-Zhou Huang、Wen-Qing Ai、Na Wei、Ling-Shuang Zhu、Zhi-Qiang Liu、Chao-Wen Zhou、Man-Fei Deng、Wen-Tao Zhang、Jia-Chen Zhang、Chun-Qing Yang、Ya-Zhuo Hu、Zhi-Tao Han、Hong-Hong Zhang、Jian-Jun Jia、Jing Wang、Fang-Fang Liu、Ke Li、Qi Xu、Mei Yuan、Hengye Man、Ziyuan Guo、Youming Lu、Kai Shu、Ling-Qiang Zhu、Dan Liu

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作者单位：

Department of Pathophysiology,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

Department of Pathology,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450002,China

Department of Pathology,School of Basic Medicine,Zhengzhou University,Zhengzhou 450002,China

The Second Affiliated Hospital,Department of Neurology,Hengyang Medical School,University of South China,Hengyang 421001,China

Beijing Key Laboratory of Aging and Geriatrics,National Clinical Research Center for Geriatric Disease,Institute of Geriatrics,Chinese PLA General Hospital and Chinese PLA Medical Academy,Beijing 100853,China

Department of Neurosurgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

Department of Neurology,Union Hospital,Huazhong University of Science and Technology,Wuhan 430022,China

Department of Biology,Boston University,Boston,MA 02215,USA

Center for Stem Cell and Organoid Medicine(CuSTOM),Division of Developmental Biology,Cincinnati Children's Hospital Medical Center,Cincinnati,OH 45229,USA

Department of Medical Genetics,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

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基金：

国家重点研发计划国家重点研发计划国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Top-Notch Young Talents Program of China of(2014)中国博士后科学基金Hubei Provincial Natural Science FoundationHubei Provincial Natural Science FoundationHubei Provincial Natural Science FoundationUniversity of South China Clinical Research 4310 ProgramScience and Technology Innovation Program of Hunan ProvinceKey Research and Development and Promotion Program of Henan Science and Technology DepartmentKey Research and Development and Promotion Program of Henan Science and Technology DepartmentKey Research and Development and Promotion Program of Henan Science and Technology DepartmentHenan Province Medical Science and Technology Research Project

项目编号：

2019YFE01212002022YFC240390582325017823714038203003282261138555317210023207096082001164820012562018M6428552022CFA0042023AFA0682020CFB65720224310NHYCG082022RC4044182102310512202102310354222102310084SBGJ202103052

出版年：

2024

DOI：

10.1093/procel/pwad056

蛋白质与细胞

CSTPCD

影响因子：0.645

ISSN：

年,卷(期)：2024.15(4)

参考文献量108