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 sen...