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
• 负责人: WEN-CHENG XIONG
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10254624
• 关键词: Actins; Action Potentials; Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein Precursor; Animal Disease Models; Behavior; Blood Circulation; Body Weight decreased; Brain; Brain Pathology; CCL1 gene; CDKN2A gene; CXCL13 gene; CXCL2 gene; Cell Aging; Cells; Chronic; Cognitive deficits; Defect; Dementia; Denervation; Development; Diagnosis; Disease; Disease Progression; Early Onset Alzheimer Disease; Encephalitis; Exhibits; Galactosidase; Genes; Gliosis; Goals; Growth Factor; Hippocampus (Brain); Homeostasis; Human; IL6 gene; Impairment; Inflammation; Inflammatory; Interleukin-1; Iron; Late Onset Alzheimer Disease; Light; Link; LoxP-flanked allele; Maintenance; Mental Depression; Metabolism; Mind; Mouse Protein; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscle Weakness; Muscle function; Mutation; Neurofibrillary Tangles; Neuroglia; Neuromuscular Junction; Pathogenesis; Pathogenicity; Pathologic; Patients; Phenotype; Plasma; Population; Process; Research; Role; Senile Plaques; Severities; Skeletal Muscle; Skeletal bone; TNF gene; TP53 gene; Testing; Tg2576; Therapeutic Intervention; Thinness; Time; Tissues; Transgenes; Transgenic Mice; Veterans; base; brain cell; cell growth; cell type; cerebrovascular amyloid; chemokine; cytokine; genetic risk factor; hepcidin; mouse model; muscle aging; muscle degeneration; muscle form; muscle strength; muscular structure; mutant; neurogenesis; neuron loss; novel; peptide hormone; promoter; protein expression; risk variant; sarcopenia; selective expression; senescence; skeletal; skeletal muscle wasting; tau-1

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.

该建议的目的是研究瑞典突变淀粉样蛋白的可能贡献 （AppSwe）在骨骼肌中，阿尔茨海默氏病（AD）的发病机理。应用是孟德尔的基因 早发广告。 App中的瑞典突变偏爱App裂解以产生淀粉样蛋白（A）。许多研究 因此，尽管应用程序和其他AD风险基因是 已知不仅在大脑中，而且在外围时间表达。 在这里，我们询问骨骼肌中的APP代谢是否改变对与广告相关的大脑有任何贡献 病理学，如果是这样，其基本机制是什么，出于以下原因。首先，尽管广告是 病理学以皮质和脑血管a斑块，含有神经原纤维的磷酸化斑块的特征 缠结，反应性神经胶质细胞相关的慢性脑感染和海马神经元丧失，AD患者 通常具有较低的瘦质量（骨骼肌的质量）和减肥，这与 痴呆和广告进展的严重程度。其次，在TG2576中对骨骼肌结构的检查，A 特征良好的AD动物模型，可普遍地表达Appswe，并发展出与广告相关的大脑 病理性缺陷，早在3-MO（月大）之前就揭示了肌肉运动表型 可以检测到的任何脑部病理缺陷。第三，除了TG2576，我们还生成了 一个有条件的转基因小鼠模型，可在CRE依赖性中appswe的细胞类型特异性表达 方式。通过将Floxed Appswe Transgene与人穿过骨骼肌中Appswe的选择性表达 骨骼-肌动蛋白（HSA）启动子驱动的CRE（TGAPPSWEHSA）不仅导致肌肉定义[例如，减少 复合肌肉动作电位（CMAP）和在3-处的神经肌肉连接（NMJ）处增加的神经支配 MO]，但还包括脑表型（例如，3-MO处的海马神经发生受损，反应性增加 7-MO皮质中的神经胶质）。这些结果不仅证明了Appswe在 抑制成人NMJ维护和加速骨骼肌老化，但也是一个单元自动的 在大脑中的作用。第四，为了了解肌肉应用如何影响脑细胞，我们表征了appswe+ 表达Appswe的肌肉和肌肉细胞（C2C12），观察到细胞感应的升高， 包括P16INK4A的增加和相关的-半乳糖苷酶（SA--GAL）和降低 C2C12细胞生长。感应相关秘书表型（SASP）的因素也增加了 tgappswehsa肌肉及其循环血。 鉴于这些观察结果，我们假设AppSwe在骨骼肌肉中的表达可能 通过增加肌肉感应和SASP因子来促进AD病理。我们将测试这个 通过实现以下三个特定目标的实现。在AIM 1中，我们将检验假设 骨骼肌中的Appswe会增加脑细胞的感受，并促进与AD相关的大脑定义。 在AIM 2中，我们将检验以下假设，即增加肌肉细胞感应有助于NMJ和大脑 Tgappswehsa小鼠的缺陷。在AIM 3中，我们将检验以下假设：SASP因素（例如肝素） 表达AppSwe的肌肉对于脑细胞感应和AD病理是必需的。 我们希望结果能够揭示肌肉appswe与AD脑病理学的新联系， 为AD开发更好的诊断和治疗干预的先决条件，以更高的速度发生 退伍军人。