Regulation of BACE1 transcytosis in hippocampal neurons

海马神经元 BACE1 转胞吞作用的调节

基本信息

  • 批准号:
    9125717
  • 负责人:
  • 金额:
    $ 23.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-15 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): BACE1 is a type I transmembrane protein that initiates Alzheimer's disease Aß production by cleavage of amyloid precursor protein (APP). Accumulating evidence demonstrates that synaptic activity dynamically regulates Aß release production near synapses. The molecular and cellular mechanisms underlying activity- dependent increase of Aß production remain largely unknown. In addition to APP, BACE1 cleaves a number of synaptic transmembrane substrates. Recently, we discovered unidirectional dendritic retrograde transport of internalized BACE1 in hippocampal neurons and found evidence that BACE1 undergoes long-range transport from somatodendritic compartment to axon, in a process termed transcytosis. Very few studies have been published on the regulation of neuronal BACE1 trafficking, and also on protein transcytosis in neurons. BACE1 undergoes post-translational S-palmitoylation, phosphorylation, and ubiquitylation. These modifications on synapse-associated proteins occur in response to synaptic activity, which, in turn, regulate dynamic protein trafficking. We hypothesize that synaptic activity modulates dynamic trafficking at the synapse and transcytosis of internalized BACE1, thus providing a crucial mechanism by which synaptic activity could promote amyloidogenic processing of APP at or near synaptic sites. The Specific Aims of this proposal are: Aim 1) To test the hypothesis that synaptic activity regulates BACE1 trafficking and transcytosis. We will use advanced live-cell imaging and FRAP methods to characterize how synaptic activity affects BACE1 localization in dendritic spines and presynaptic terminals and the local dynamics of BACE1 internalization and recycling at the synapse. In parallel, we will assay transcytosis of internalized BACE1 using microfluidic culture system. Aim 2) To test the hypothesis that synaptic activity dynamically modulates BACE1 post-translational modifications. We will investigate how synaptic activity modulates dynamic modifications within the cytosolic tail of endogenous BACE1. We will confirm and extend the findings by performing trafficking studies (as in Aim 1) in neurons expressing BACE1 bearing mutations within the sites of S-palmitoylation, phosphorylation, and ubiquitylation. Our proposal is timely, unique, and highly innovative because we were the first to describe BACE1 transcytosis in recycling endosomes. We now propose to extend our findings to study how synaptic activity modulates this highly unusual mode of protein trafficking. Our goal to investigate synaptic regulation of BACE1 is also highly significant because endogenous BACE1 and transgene expressed BACE1-YFP predominantly localize to presynaptic terminals in vivo, and BACE1 accumulates in dystrophic presynaptic terminals near senile plaques in the brains of individuals with AD. Thus, investigating how synaptic activity is coupled to BACE1 trafficking and axonal targeting is highly relevant to mechanisms underlying Alzheimer's disease pathogenesis as well as for BACE1 processing of its multiple neuronal substrates under physiological and pathological conditions.


项目成果

期刊论文数量(0)
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专利数量(0)

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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

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
  • 财政年份:
    2022
  • 资助金额:
    $ 23.7万
  • 项目类别:
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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 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:
    $ 23.7万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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