Defective lysosome acidification in dystrophic neurites in Alzheimer's disease contributes to failure of autophagy

阿尔茨海默病营养不良的神经突中溶酶体酸化缺陷导致自噬失败

基本信息

  • 批准号:
    10670489
  • 负责人:
  • 金额:
    $ 73.88万
  • 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:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Alzheimer’s disease is a national crisis and the burden of this terrible disease is rising. After decades of failure to produce a disease modifying treatment for Alzheimer’s disease, it is critical that we identify drug targets that are linked to causal mechanisms underlying the diverse neuropathological substrates of Alzheimer’s disease. Our research focuses on the function of lysosomes within an axonal structure called a dystrophic neurite. Dystrophic neurites form when axon segments pass near a β-amyloid plaque and become distended and clogged with lysosomes and related organelles. Tau aggregates are also present in some dystrophic neurites, so this pathology seems to link the major pathological hallmarks of Alzheimer’s disease. Because lysosomes are critical for protein homeostasis, we hypothesize that loss of function of these lysosomes is a key step in the formation of toxic protein aggregates. We demonstrated a pattern of changes in the function this pool of lysosomes which could be explained by failure of acidification, so in this proposal we will evaluate 1) whether lysosomes in dystrophic neurites are able to acidify and what molecular mechanisms may underlie failed acidification, 2) whether loss of lysosome acidification results in defective autophagy and accumulation of pathologic autophagic intermediates within dystrophic neurites and 3) the degree to which a novel Alzheimer’s disease genetic risk factor, RBFOX1, contributes to altered autophagy and pH regulation in neuronal lysosomes. For each of these aims, we leverage advanced in vitro methods including organotypic brain slice cultures from adult model animals and three-dimensional human neuronal cultures derived from induced pluripotent stem cells grown in a custom designed hydrogel matrix. Using live-imaging, we will quantitatively measure the pH in lysosomes in dystrophic neurites. We will conduct detailed neuropathological studies simultaneously in human and mouse model systems to identify altered distribution of vacuolar ATPase subunits, ARL1 and Golgin A4 which are key regulators of autophagy, and RBFOX1. Additionally, we want to understand the cognitive and neuropathological associations of each component of the molecular pathways that contribute to failed acidification, defective autophagy and tau aggregation, so we will leverage RNAseq and proteomic data from large clinical studies, in particularly the Religious Orders Study/Memory and Alzheimer’s Project, to ensure these pathways are functionally important. These synergistic streams of data will converge to robustly establish the mechanism and consequence of loss of lysosome acidification in dystrophic neurites and identify molecular targets for future drug discovery efforts.
阿尔茨海默病是一场全国性的危机,这种可怕疾病的负担正在上升。后

项目成果

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Matthew Schrag其他文献

Matthew Schrag的其他文献

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{{ truncateString('Matthew Schrag', 18)}}的其他基金

Defective lysosomal membrane fission mediates axonal lysosome accumulation in dystrophic neurites in Alzheimer's disease.
溶酶体膜裂变缺陷介导阿尔茨海默病营养不良神经突中轴突溶酶体的积累。
  • 批准号:
    10674842
  • 财政年份:
    2019
  • 资助金额:
    $ 73.88万
  • 项目类别:
Defective lysosomal membrane fission mediates axonal lysosome accumulation in dystrophic neurites in Alzheimer's disease.
溶酶体膜裂变缺陷介导阿尔茨海默病营养不良神经突中轴突溶酶体的积累。
  • 批准号:
    9982738
  • 财政年份:
    2019
  • 资助金额:
    $ 73.88万
  • 项目类别:
Defective lysosomal membrane fission mediates axonal lysosome accumulation in dystrophic neurites in Alzheimer's disease.
溶酶体膜裂变缺陷介导阿尔茨海默病营养不良神经突中轴突溶酶体的积累。
  • 批准号:
    9812548
  • 财政年份:
    2019
  • 资助金额:
    $ 73.88万
  • 项目类别:
Defective lysosomal membrane fission mediates axonal lysosome accumulation in dystrophic neurites in Alzheimer's disease.
溶酶体膜裂变缺陷介导阿尔茨海默病营养不良神经突中轴突溶酶体的积累。
  • 批准号:
    10406342
  • 财政年份:
    2019
  • 资助金额:
    $ 73.88万
  • 项目类别:

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