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.
这项提案的目的是调查瑞典突变淀粉样前体蛋白的可能贡献, (APPswe)与阿尔茨海默病(AD)发病机制的关系。App是一种孟德尔基因, 早发性AD App中的瑞典突变有利于APP切割以产生β-淀粉样蛋白(A β)。许多研究表明, 因此,AD一直专注于A β对大脑的影响,尽管App和其他AD风险基因是 已知不仅在脑中表达,而且在外周组织中表达。 在这里,我们询问骨骼肌中APP代谢的改变是否对AD相关的大脑有任何贡献。 病理学,如果是这样的话,其潜在机制是什么,原因如下。首先,虽然AD 病理学特征为皮质和脑血管A β斑块,含磷酸化tau蛋白的神经胶质细胞, 缠结、反应性胶质细胞相关慢性脑炎症和海马神经元丢失、AD患者 通常有较低的瘦质量(骨骼肌和骨骼的质量)和体重减轻,这与 痴呆和AD进展的严重程度。第二,检查Tg 2576,a 一种充分表征的AD动物模型,该模型普遍表达APPswe,并发育出一些AD相关的大脑, 病理缺陷,早在3-MO(月龄)时就显示出肌无力表型, 任何可以检测到的脑部病理缺陷第三,除了TG 2576,我们还生成了 Cre依赖性细胞特异性表达APPswe的条件转基因小鼠模型 方式APPswe基因与人骨骼肌杂交选择性表达APPswe 骨骼肌肌动蛋白(HSA)启动子驱动的Cre(TgAPPsweHSA)不仅导致肌肉缺陷[例如,减少 复合肌肉动作电位(CMAP)和神经肌肉接头(NMJ)的去神经支配增加, MO],但也包括脑表型(例如,3-MO时海马神经发生受损, 7-MO皮质神经胶质增生)。这些结果不仅证明了APPswe在细胞内的自主作用, 抑制成人NMJ维持和加速骨骼肌老化,但也是一个细胞非自主 在大脑中的作用。第四,为了了解肌肉APPswe如何影响脑细胞,我们描述了APPswe+ 肌肉和表达APPswe的肌肉细胞(C2 C12),并观察到细胞衰老的升高, 包括p16 Ink 4a和衰老相关的β-半乳糖苷酶(SA-β-Gal)的增加和 C2 C12细胞生长。衰老相关的分泌表型因子(SASP)也增加, TgAPPsweHSA肌肉和它们的循环血液。 根据这些观察结果,我们假设骨骼肌中APPswe的表达可能 通过增加肌肉衰老和SASP因子来促进AD病理学。我们将测试这个 通过实现以下三个具体目标的假设。在目标1中,我们将检验假设 骨骼肌中的APPswe增加了脑细胞衰老,并促进了大脑中与AD相关的缺陷。 在目标2中,我们将测试增加的肌肉细胞衰老有助于NMJ和大脑的假设。 TgAPPsweHSA小鼠中的缺陷。在目标3中,我们将检验SASP因子,如铁调素, 表达APPsw的肌肉对于脑细胞衰老和AD病理是必需的。 我们希望,这些结果将揭示肌肉APPswe与AD脑病理学的新联系, 这是开发更好的AD诊断和治疗干预的先决条件, 老兵

项目成果

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WEN-CHENG XIONG其他文献

WEN-CHENG XIONG的其他文献

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{{ 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:
    8842912
  • 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:
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:

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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
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细菌肌动蛋白分离质粒的结构基础
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    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
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多种植物肌动蛋白的差异表达
  • 批准号:
    7931495
  • 财政年份:
    2009
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研究肌动蛋白和微管如何协调及其相关性。
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拟南芥生殖肌动蛋白的抑制
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    6655612
  • 财政年份:
    2003
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Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
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肌球蛋白与单体肌动蛋白的相互作用
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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:
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  • 财政年份:
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