# Swedish APP mutation and NMJ decline in Alzheimer's disease

> **NIH NIH RF1** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $2,591,248

## Abstract

Alzheimer's disease (AD) is the most common form of dementia, affecting ~10% of the
population over 65 years of age. AD is a systemic disorder that affects the brain and
peripheral tissues. Patients with AD suffer from declined memory, cognitive deficits, and
changes in personality. In addition, AD is often associated with reduced muscle strength,
even at early stages. In some AD patients, muscle strength is reduced without loss of
muscle mass. However, pathological mechanisms of reduced muscle strength are not well
understood. Muscle contraction requires the efficient neurotransmission at the
neuromuscular junction (NMJ), a synapse between motor nerve terminals and skeletal
muscle fibers. Its formation requires a proteoglycan from motor nerves, agrin, which binds
to LRP4 to activate the receptor tyrosine kinase MuSK. We and others showed recently that
agrin signaling is also necessary for NMJ maintenance and is compromised in
neuromuscular disorders and in aged mice. Interestingly, APP, a risk gene of AD, is
expressed in skeletal muscles and becomes progressively concentrated at the NMJ after
birth. APP and its homolog APP-like protein 2 (APLP2) regulate NMJ formation. APP can
interact with LRP4 to promote agrin-induced AChR clustering. To understand pathological
mechanisms of muscle weakness in AD, we generated HSA-APPswe that specifically
express in muscles mutant APP with Swedish mutations (APPswe). Remarkably, HSA-
APPswe mice were weak in muscle contractile force, in particular that by nerve
stimulation, and NMJs became denervated with compromised neuromuscular transmission.
Initial mechanistic studies revealed diminished agrin signaling and increased cellular
senescence, a process originally defined as cell growth arrest but increasingly implicated in
ageing-associated processes. While these findings are exciting, they raise many questions.
Is muscle weakness in HSA-APPswe mice due to NMJ decline or vice versa? What is the
primary target of APPswe, pre- or post-synaptic function? How does APPswe impair the
NMJ, by diminishing agrin signaling or by enhancing cellular senescence, or both? And,
how? These questions will be addressed in this proposal. The overarching hypothesis at test
is that APPswe causes NMJ decline in aged mice by impairing agrin signaling and causing
cellular senescence in the muscle. To test this innovative hypothesis, we will determine
whether APPswe promotes NMJ decline by impairing agrin-LRP4 signaling and by
increasing muscle cell senescence. Results will uncover new pathological mechanisms by
which AD-association APP mutations damage the NMJ and reduce muscle strength and
reveal whether restoring agrin-LRP4 signaling and/or inhibiting cellular senescence prevent
NMJ decline and thus improve muscle strength. Such knowledge is prerequisite to
development of effective therapeutic interventions for muscle weakness in AD patients.

## Key facts

- **NIH application ID:** 10156645
- **Project number:** 2RF1AG051510-07
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** WEN-CHENG XIONG
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,591,248
- **Award type:** 2
- **Project period:** 2015-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156645

## Citation

> US National Institutes of Health, RePORTER application 10156645, Swedish APP mutation and NMJ decline in Alzheimer's disease (2RF1AG051510-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10156645. Licensed CC0.

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