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.

Public Health Relevance

The proposed research is to test the hypothesis that APP Swedish mutation causes NMJ decline in aged mice by impairing agrin signaling and causing cellular senescence in the muscle. Results will uncover new pathological mechanisms of AD-associated muscle weakness.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Williams, John
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Case Western Reserve University
Schools of Medicine
United States
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