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.

该提案的目的是研究瑞典突变淀粉样前体蛋白的可能贡献 （APPswe）在骨骼肌中与阿尔茨海默病（AD）的发病机制有关。App 是孟德尔基因。 瑞典的早发型 AD 突变有利于 APP 裂解产生 β-淀粉样蛋白 (A)。 因此，AD 一直关注 A 对大脑的影响，尽管 App 和其他 AD 风险基因 已知不仅在大脑中表达，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 相关大脑有任何贡献 病理学，如果是的话，其根本机制是什么，原因如下：首先，虽然AD是。 病理学特征为皮质和脑血管斑块、含有磷酸tau的神经原纤维 AD 患者的缠结、反应性神经胶质细胞相关的慢性脑炎症和海马神经元损失 通常具有较低的瘦体重（骨骼肌和骨骼的质量）和体重减轻，这与 其次，检查 Tg2576 中的骨骼肌结构。 特征明确的 AD 动物模型，普遍表达 APPswe，并发育出一些与 AD 相关的大脑 病理缺陷，早在 3-MO（月龄）、几个月前就显示出肌肉无力表型 第三，除了 Tg2576 之外，我们还生成了任何可检测到的脑病理缺陷。 能够以 Cre 依赖性细胞类型特异性表达 APPswe 的条件转基因小鼠模型 通过将 floxed APPswe 转基因与人类杂交，在骨骼肌中选择性表达 APPswe。 骨骼 α-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) 去神经支配增加 (3-) MO]，还有大脑表型（例如，3-MO 时海马神经发生受损以及反应性增加） 7-MO 皮质中的胶质细胞增生）这些结果不仅证明了 APPswe 在细胞自主作用中的作用。 抑制成人 NMJ 维持并加速骨骼肌衰老，也是细胞非自主的 第四，为了了解肌肉 APPswe 如何影响脑细胞，我们对 APPswe+ 进行了表征。 表达 APP 的肌肉和肌肉细胞 (C2C12)，并观察到细胞衰老的增加， 包括 p16Ink4a 和衰老相关 β-半乳糖苷酶 (SA-β-Gal) 的增加以及 C2C12 细胞的生长因子也增加了。 TgAPPsweHSA 肌肉及其循环血液。 根据这些观察，我们发现骨骼肌中的 APPswe 表达可能 通过增加肌肉衰老和 SASP 因素来促进 AD 病理，我们将对此进行测试。 通过实现以下三个具体目标来检验假设。在目标 1 中，我们将检验假设。 骨骼肌中的 APPswe 会增加脑细胞衰老并促进与 AD 相关的大脑缺陷。 在目标 2 中，我们将检验肌肉细胞衰老增加有助于 NMJ 和大脑的假设 在目标 3 中，我们将测试 SASP 因子（例如铁调素）的假设。 表达 APPswe 的肌肉对于脑细胞衰老和 AD 病理学是必需的。 我们希望结果能够揭示肌肉 APP 与 AD 脑病理学之间的新联系，即 为 AD 的发生率较高而制定更好的诊断和治疗干预措施的先决条件 退伍军人。