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Understanding Alzheimer's Disease in the Context of the Aging Brain

Understanding Alzheimer's Disease in the Context of the Aging Brain
在大脑老化的背景下了解阿尔茨海默病
批准号:
9856238
负责人:
ANA MARIA CUERVO
金额:
$123.17万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-15 至 2022-08-31

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英文摘要
Abstract This proposal investigates the role and impact of defective maintenance of protein homeostasis (proteostasis) of the aging brain, in the development and progression of Alzheimer’s disease. Disturbances in the systems that maintain neuronal proteostasis have been observed in Alzheimer’s disease, but the extent to which loss of proteostasis in the aging brain constitutes a risk factor for development of Alzheimer’s disease remains unknown. We will focus in chaperone-mediated autophagy (CMA), a protein quality control system that mediates selective degradation of cytosolic proteins in lysosomes. We have previously found that CMA activity decreases with age and that restoring CMA activity in old mice livers prevents their degeneration and preserves organ function. We propose that 1) the physiological decline of CMA with age increases the susceptibility of the aging brain to Alzheimer’s disease-related pathology and that 2) interventions to restore normal CMA activity in the aging brain will prevent or slow down progression of Alzheimer’s disease neurodegeneration. To test this hypothesis we intend to: 1) determine the spatiotemporal sequence of CMA changes in the aging brain to identify areas of higher susceptibility to proteotoxicity and points of “no return” to proteostasis; 2) investigate if characteristics of the Alzheimer’s disease brain are phenocopied by neuronal CMA blockage; 3) test if genetic or chemical enhancement of CMA in the aging brain increases its resistance to AD-relevant proteotoxicity and improves neuronal homeostasis and function. Significance: This study will elucidate how functional decline of CMA contributes to brain aging and if it increases Alzheimer’s disease risk in the aging brain. Our findings could help in developing new approaches to preserve old brain homeostasis and function and reduce its risk to Alzheimer’s disease neuropathology.
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Decreased Protein Degradation in Aging
Decreased Protein Degradation in Aging
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
  • 批准号:
    10434057
  • 项目类别:
  • 资助金额:
    $72.53万
  • 财政年份:
    2017
  • 负责人:
    ANA MARIA CUERVO
  • 依托单位:
Molecular and Cellular Mechanisms of the Lysosomal Storage Disease Cystinosis
  • 批准号:
    10683169
  • 项目类别:
  • 资助金额:
    $72.53万
  • 财政年份:
    2017
  • 负责人:
    ANA MARIA CUERVO
  • 依托单位:
国内基金
海外基金
年轻血清介导血管内皮细胞Cdk5负调控高反应性中性粒细胞浸润入脑减轻Alzheimer’s病的机制研究
  • 批准号:
    82271473
  • 项目类别:
    面上项目
  • 资助金额:
    52万元
  • 批准年份:
    2022
  • 负责人:
    祁方昉
  • 依托单位:
雌激素GPR30受体通过调节神经免疫治疗Alzheimer's病的机制研究
基于AKT/mTOR/HIF-1a信号轴调控糖代谢重编程探讨补阳还五汤减轻炎症防治Alzheimer病的机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    55万元
  • 批准年份:
    2021
  • 负责人:
    杨琳
  • 依托单位:
流感疫苗联合PD-1抗体在Alzheimer’s病治疗中的作用及机制研究
  • 批准号:
    81971021
  • 项目类别:
    面上项目
  • 资助金额:
    55.0万元
  • 批准年份:
    2019
  • 负责人:
    祁方昉
  • 依托单位: