# Skeletal Muscular Swedish Mutant APP in Alzheimer's Disease Development

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2022 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10254624
- **Project number:** 1I01BX005642-01
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** WEN-CHENG XIONG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254624

## Citation

> US National Institutes of Health, RePORTER application 10254624, Skeletal Muscular Swedish Mutant APP in Alzheimer's Disease Development (1I01BX005642-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10254624. Licensed CC0.

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