The role of Alzheimer's disease GWAS risk factor BIN1 in tau neuropathology and propagation in vivo

阿尔茨海默病 GWAS 危险因子 BIN1 在 tau 神经病理学和体内传播中的作用

基本信息

  • 批准号:
    10448676
  • 负责人:
  • 金额:
    $ 217.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

BIN1, the most significant late-onset Alzheimer’s disease (LOAD) susceptibility locus identified via GWAS, encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. BIN1 can directly bind to tau, leading to the suggestion that BIN1 might influence AD tangle pathology. However, we and others have failed to find evidence directly linking cytosolic BIN1·tau interaction to AD risk. In contrast, compelling in vitro evidence suggests that BIN1’s function in membrane dynamics limits pathogenic tau seed uptake and influences tau release. This indicates that neuronal BIN1 might regulate tau pathology propagation. In vivo evidence to support this notion is still lacking. In order to elucidate how BIN1 function relates to disease risk for AD, it is imperative to better understand BIN1’s role in tau pathogenesis and disease progression using appropriate animal models. Our preliminary characterization of tau pathogenesis in Bin1-cKO mice reveals a complex picture: the loss of BIN1 expression in tau transgenic mice exacerbated tau pathology in the spinal cord, accelerated disease progression, and caused early death. Intriguingly, BIN1 loss also attenuated brain atrophy and protected the hippocampus from neuroinflammation, synapse, and neuronal loss, thus, profoundly reducing tau neuropathology in select regions. These intriguing findings need to be extended because of their direct clinical implications. Our central hypothesis is that BIN1 exerts its function as a risk factor by modulating tau pathophysiology in a region-specific manner. Since BIN1 is a potential target for future therapies, the overall objective of this investigation is to characterize BIN1 modulation of tau neuropathology in vivo and gain molecular insights into region-specific BIN1 functions. The goal of Aim 1 is to generate cell-type-specific inducible Bin1-cKO using CamK- and PLP-CreERT-drivers, characterize tau pathogenesis using in vivo longitudinal MR imaging and detailed neuropathology and test the hypothesis that BIN1 expression modulates tau neuropathology in select brain regions. Aim 2 studies will apply complementary stereotaxic injection approaches to directly test the hypothesis that BIN1 exerts a region-specific influence on neuron-to-neuron tau spread or influences uptake and pathology propagation via mutant tau template interaction. Aim 3 studies will perform molecular analyses through bulk and digital spatial transcriptomic strategies to map cell-autonomous and non-cell-autonomous disease-related gene expression changes and elucidate functional pathways involved in BIN1-mediated region-specific pathology modulation. This timely and unique proposal is highly innovative. This investigation using multiple Bin1-cKO mice represents the most direct in vivo approach to rigorously investigate BIN1’s involvement in the biological pathways of tau neuropathology. We believe that the successful completion of the proposed investigation will fill significant gaps in our understanding of BIN1 as a risk factor for LOAD and guide future functional characterizations of molecular pathways and pathogenic mechanisms regulated by this major LOAD risk gene.
BIN1,最显著的晚发型阿尔茨海默病(LOAD)易感位点

项目成果

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GOPAL THINAKARAN其他文献

GOPAL THINAKARAN的其他文献

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{{ truncateString('GOPAL THINAKARAN', 18)}}的其他基金

High-plex Protein and Gene Expression Digital Spatial Profiler for Core Facility
用于核心设施的高复杂蛋白质和基因表达数字空间分析仪
  • 批准号:
    10177265
  • 财政年份:
    2021
  • 资助金额:
    $ 217.46万
  • 项目类别:
Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology
GWAS 危险因子 BIN1 在阿尔茨海默病神经病理学中的细胞自主和非细胞自主作用
  • 批准号:
    9198396
  • 财政年份:
    2016
  • 资助金额:
    $ 217.46万
  • 项目类别:
Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology
GWAS 危险因子 BIN1 在阿尔茨海默病神经病理学中的细胞自主和非细胞自主作用
  • 批准号:
    10176956
  • 财政年份:
    2016
  • 资助金额:
    $ 217.46万
  • 项目类别:
Regulation of BACE1 transcytosis in hippocampal neurons
海马神经元 BACE1 转胞吞作用的调节
  • 批准号:
    9125717
  • 财政年份:
    2015
  • 资助金额:
    $ 217.46万
  • 项目类别:
Multi-purpose Superresolution Microscope for Core Facility
用于核心设施的多用途超分辨率显微镜
  • 批准号:
    8246831
  • 财政年份:
    2012
  • 资助金额:
    $ 217.46万
  • 项目类别:
Cell Biology of Presenilin 1 and Associated Proteins
早老素 1 和相关蛋白的细胞生物学
  • 批准号:
    7919038
  • 财政年份:
    2009
  • 资助金额:
    $ 217.46万
  • 项目类别:
Mouse model for neuroprotection
神经保护小鼠模型
  • 批准号:
    7019332
  • 财政年份:
    2006
  • 资助金额:
    $ 217.46万
  • 项目类别:
Mouse model for neuroprotection
神经保护小鼠模型
  • 批准号:
    7229860
  • 财政年份:
    2006
  • 资助金额:
    $ 217.46万
  • 项目类别:
Cell Biology of Presenilin 1 and Associated Proteins
早老素 1 和相关蛋白的细胞生物学
  • 批准号:
    6559483
  • 财政年份:
    2002
  • 资助金额:
    $ 217.46万
  • 项目类别:
Cell Biology of Presenilin 1 and Associated Proteins
早老素 1 和相关蛋白的细胞生物学
  • 批准号:
    6755908
  • 财政年份:
    2002
  • 资助金额:
    $ 217.46万
  • 项目类别:

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