Skeletal Muscular Swedish Mutant APP in Alzheimer's Disease Development

瑞典骨骼肌突变体 APP 在阿尔茨海默病发展中的作用

基本信息

项目摘要

The goal of this proposal is to investigate possible contributions of Swedish mutant amyloid precursor protein (APPswe) in skeletal muscles to the pathogenesis of Alzheimer’s disease (AD). App is a Mendelian gene for early-onset AD. Swedish mutations in App favor APP cleavage to generate -amyloid (A). Much research on AD has thus been focused on the impact of A on the brain, even though App and other AD risk genes are known to be expressed not only in the brain, but also in periphery tissues. Here, we asked if altered APP metabolism in skeletal muscles has any contribution to AD-relevant brain pathology, and if so, what are the underlying mechanisms, for the following reasons. First, although AD is pathologically characterized by cortical and cerebrovascular A plaques, phospho-tau containing neurofibrillary tangles, reactive glial cell-associated chronic brain inflammation, and hippocampal neuronal loss, AD patients often have lower lean-mass (mass of skeletal muscle and bone) and weight-loss, which are associated with the severity of dementia and AD progression. Second, examinations of skeletal muscle structures in Tg2576, a well-characterized AD animal model that expresses APPswe ubiquitously and develops some AD-relevant brain- pathologic deficits, revealed muscle-weakness phenotype as early as 3-MO (month old), months before any brain-pathologic defect that can be detected. Third, in addition to Tg2576, we generated a conditional transgenic mouse model capable of cell-type specific expression of APPswe in Cre-dependent manner. Selective expression of APPswe in skeletal muscles by crossing floxed APPswe transgene with human skeletal -actin (HSA) promoter driven Cre (TgAPPsweHSA) resulted in not only muscle deficits [e.g., reduced compound muscle action potential (CMAP) and increased denervation at neuromuscular junction (NMJ) at 3- MO], but also brain phenotypes (e.g., impaired hippocampal neurogenesis at 3-MO and increased reactive gliosis in cortex of 7-MO). These results demonstrate not only a cell autonomous role of APPswe in suppressing adult NMJ maintenance and accelerating skeletal muscle aging, but also a cell-non-autonomous role in the brain. Fourth, to understand how muscle APPswe affects brain cells, we characterized APPswe+ muscles and muscle cells (C2C12) expressing APPswe, and observed an elevation of cellular senescence, including increases in p16Ink4a and senescence associated -galactosidase (SA--Gal) and a decrease in C2C12 cell growth. The factors of senescence associated secretary phenotype (SASP) were also increased in TgAPPsweHSA muscles and their circulation blood. In light of these observations, we hypothesize that APPswe expression in skeletal muscles may contribute to AD pathology by increasing muscle senescence and SASP factors. We will test this hypothesis by the accomplishment of the following three specific aims. In Aim 1, we will test the hypothesis that APPswe in skeletal muscles increases brain cell senescence and promotes AD-relevant deficits in the brain. In Aim 2, we will test the hypothesis that increased muscle cellular senescence contributes to NMJ and brain deficits in TgAPPsweHSA mice. In Aim 3, we will test the hypothesis that SASP factors, such as hepcidin, from APPswe-expressing muscles are necessary for brain cell senescence and AD pathology. It is our hope that the results will reveal a novel link of muscular APPswe with AD brain pathology, a prerequisite to develop better diagnosis and therapeutic intervention for AD that occurs at higher rate among veterans.
本建议的目的是调查瑞典突变淀粉样蛋白前体蛋白的可能贡献

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 }}

WEN-CHENG XIONG其他文献

WEN-CHENG XIONG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 }}

{{ truncateString('WEN-CHENG XIONG', 18)}}的其他基金

Skeletal Muscular Swedish Mutant APP in Alzheimer's Disease Development
瑞典骨骼肌突变体 APP 在阿尔茨海默病发展中的作用
  • 批准号:
    10254624
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Retromer deficiency and Alzheimer's disease pathology
逆转录酶缺乏与阿尔茨海默病病理学
  • 批准号:
    9605932
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
APP as a common denominator for Alzheimer's disease and osteoporosis
APP 是阿尔茨海默病和骨质疏松症的共同点
  • 批准号:
    9903240
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
APP as a common denominator for Alzheimer's disease and osteoporosis
APP 是阿尔茨海默病和骨质疏松症的共同点
  • 批准号:
    9607371
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
APP as a common denominator for Alzheimer's disease and osteoporosis
APP 是阿尔茨海默病和骨质疏松症的共同点
  • 批准号:
    9323223
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Retromer deficiency and Alzheimer's disease pathology
逆转录酶缺乏与阿尔茨海默病病理学
  • 批准号:
    9059562
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Retromer deficiency and Alzheimer's disease pathology
逆转录酶缺乏与阿尔茨海默病病理学
  • 批准号:
    9486649
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Retromer deficiency and Alzheimer's disease pathology
逆转录酶缺乏与阿尔茨海默病病理学
  • 批准号:
    8708256
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Retromer deficiency and Alzheimer's disease pathology
逆转录酶缺乏与阿尔茨海默病病理学
  • 批准号:
    8842912
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Mechanisms of neuromuscular junction formation
神经肌肉接头形成机制
  • 批准号:
    10267688
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

相似海外基金

A novel motility system driven by two classes of bacterial actins MreB
由两类细菌肌动蛋白 MreB 驱动的新型运动系统
  • 批准号:
    22KJ2613
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
The structural basis of plasmid segregation by bacterial actins
细菌肌动蛋白分离质粒的结构基础
  • 批准号:
    342887
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
    Operating Grants
The structural basis for plasmid segregation by bacterial actins
细菌肌动蛋白分离质粒的结构基础
  • 批准号:
    278338
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Operating Grants
Cytoplasmic Actins in Maintenance of Muscle Mitochondria
细胞质肌动蛋白在维持肌肉线粒体中的作用
  • 批准号:
    8505938
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Differential Expression of the Diverse Plant Actins
多种植物肌动蛋白的差异表达
  • 批准号:
    7931495
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Studies on how actins and microtubules are coordinated and its relevancy.
研究肌动蛋白和微管如何协调及其相关性。
  • 批准号:
    19390048
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
  • 批准号:
    6655612
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
  • 批准号:
    6546977
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
Interaction of myosin with monomeric actins
肌球蛋白与单体肌动蛋白的相互作用
  • 批准号:
    5311554
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
  • 批准号:
    6316669
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了