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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

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

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