Mechanisms of Age-Related Microglial Impairment and Rejuvenation in Alzheimer's Disease

阿尔茨海默病中与年龄相关的小胶质细胞损伤和复兴的机制

基本信息

  • 批准号:
    9608519
  • 负责人:
  • 金额:
    $ 4.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-02 至 2021-08-01
  • 项目状态:
    已结题

项目摘要

Project Summary Age is the main risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder rapidly increasing in both incidence and prevalence as the population becomes older. Unfortunately, AD is the only top ten cause of death with no effective treatments. Therefore, the development of disease-altering treatments for AD is an urgent and unmet need. Although the exact etiology of AD is unknown, microglia, the tissue-resident macrophages of the brain, have been implicated in disease pathogenesis based on the observation that genetic variants in several microglia-specific genes significantly alter disease risk. In the healthy brain, microglia maintain homeostasis through multiple modalities including phagocytic clearance of pathogens, apoptotic cells, and debris. In AD brains and age-matched clinically-unimpaired brains alike, microglia are dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired phagocytic degradation of debris. These findings suggest that the general decline in phagocytosis with age might underlie pathological neurodegeneration. However, the mechanisms of age-related microglial dysfunction are poorly understood. This proposal aims to elucidate the mechanisms of impaired microglial phagocytosis in the aging brain and to uncover therapeutic strategies to reverse this impairment in AD. Preliminary data suggest that cell-surface sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia. Aim 1 combines biochemical and genetic tools to identify upstream and downstream signaling partners that transduce the anti- phagocytic effect of sialic acid on aged microglia. Aim 2 will evaluate the therapeutic potential of blocking the interaction between cell-surface sialic acid and its cognate receptor on microglia to promote phagocytosis and ameliorate cognitive decline in a mouse model of AD. These experiments will elucidate a mechanism of microglial dysfunction during normal aging with direct translational implications for patients with AD.
项目摘要 年龄是阿尔茨海默病(AD)的主要危险因素,AD是一种神经退行性疾病,在 随着人口老龄化,发病率和流行率都有所下降。不幸的是,AD是唯一排名前十的原因 在没有有效治疗的情况下死亡。因此,开发AD的疾病改变治疗方法是一种 迫切的和未得到满足的需求。尽管阿尔茨海默病的确切病因尚不清楚,但组织驻留的小胶质细胞 大脑的巨噬细胞,已经被认为与疾病的发病机制有关,这是基于观察到的 几个小胶质细胞特异性基因的遗传变异显著改变了疾病风险。在健康的大脑中, 小胶质细胞通过多种方式维持动态平衡,包括吞噬清除病原体, 凋亡的细胞和碎片。在阿尔茨海默病和年龄匹配的临床正常脑中,小胶质细胞 营养不良,活动不足,并有溶酶体沉积,表明吞噬细胞降解受损 碎片的碎片。这些发现表明,随着年龄的增长,吞噬功能的普遍下降可能是病理性的基础。 神经退行性变。然而,与年龄相关的小胶质细胞功能障碍的机制却知之甚少。 这一建议旨在阐明衰老脑中小胶质细胞吞噬功能受损的机制,并 发现逆转AD患者这种损害的治疗策略。初步数据显示,细胞表面 唾液酸是一种免疫调节的糖链修饰物,可抑制衰老小胶质细胞的吞噬作用。AIM 1联合收割机 生化和遗传工具,以确定上游和下游的信号伙伴,转导反式 唾液酸对衰老小胶质细胞的吞噬作用。目的2将评估阻断的治疗潜力 细胞表面唾液酸与其同源受体相互作用促进小胶质细胞吞噬功能 改善阿尔茨海默病小鼠模型的认知衰退。这些实验将阐明一种 正常衰老过程中的小胶质细胞功能障碍对AD患者有直接的翻译意义。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

John Vincent Pluvinage其他文献

John Vincent Pluvinage的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 4.31万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了