课题基金 / 基金详情

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

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
批准号:
10448676
负责人:
GOPAL THINAKARAN
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
项目状态:
未结题
起止时间:
2022-06-01 至 2025-05-31

项目摘要

项目成果

GOPAL THINAKARAN的其他基金

相似基金

相关文献

中文摘要
翻译
点击翻译按钮获取中文摘要
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
High-plex Protein and Gene Expression Digital Spatial Profiler for Core Facility
  • 批准号:
    10177265
  • 项目类别:
  • 资助金额:
    $45.0万
  • 财政年份:
    2021
  • 负责人:
    GOPAL THINAKARAN
  • 依托单位:
Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology
  • 批准号:
    9198396
  • 项目类别:
  • 资助金额:
    $206.06万
  • 财政年份:
    2016
  • 负责人:
    GOPAL THINAKARAN
  • 依托单位:
Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology
  • 批准号:
    10176956
  • 项目类别:
  • 资助金额:
    $87.59万
  • 财政年份:
    2016
  • 负责人:
    GOPAL THINAKARAN
  • 依托单位:
Regulation of BACE1 transcytosis in hippocampal neurons
  • 批准号:
    9125717
  • 项目类别:
  • 资助金额:
    $23.7万
  • 财政年份:
    2015
  • 负责人:
    GOPAL THINAKARAN
  • 依托单位:
国内基金
海外基金
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
  • 依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
    雷芬芳
  • 依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    万荣
  • 依托单位: