Neuromuscular Dysfunction as a Novel Indicator for Alzheimer's Disease and Response to Intervention in the 5xFAD Model

Abstract

Alzheimer's disease (AD) develops along a continuum that spans years to decades before cognitive decline and clinical diagnosis. Preclinical AD is often associated with decreased muscle function and mitochondrial respiration, but the cause of these peripheral phenotypes in a brain disease remains unclear. Exercise promotes muscle, mitochondrial, and cognitive health, and is proposed as a potential therapeutic for AD. This study investigates skeletal muscles adaptation to exercise in an AD-like context using 5xFAD mice, an AD model developing early pathology and cognitive impairments around 6 months of age. We examined in vivo neuromuscular function in both muscle and the sciatic nerve, and exercise adaptations (mitochondrial respiration and RNA sequencing) before overt cognitive impairment. We found that 5xFAD mice develop neuromuscular dysfunction as early as 4 months of age, characterized by impaired nerve- stimulated muscle torque production and sciatic nerve compound action potential. Additionally, skeletal muscle in 5xFAD mice showed sex-dependent altered adaptive responses to exercise training without cognitive impairment. Given these findings, we hypothesized that voluntary wheel running or an acetylcholinesterase inhibitor donepezil treatment, started before neuromuscular decline, would delay neuromuscular impairment in 5xFAD mice. Using 3-month-old 5xFAD and wild type (WT) littermates, we provided voluntary wheel access for 4 weeks and assessed exercise capacity, tibial nerve- stimulated plantar flexion torque, and sciatic nerve compound action potential at 4 months. Additionally, we investigated markers of AD-like pathology, such as amyloid- beta and neurofilament light chain. In a separate cohort, we treated 3-month-old 5xFAD mice with donepezil or placebo daily for 4 weeks and assessed similar outcomes. Our data show that both interventions delay neuromuscular impairment from 3 to 4 months but do not improve muscle-torque production as seen in exercise-trained WT mice. Neither intervention altered markers of AD-like pathology. Declines in peripheral systems, such as skeletal muscle, may be preclinical identifiers for AD, and interventions like exercise or acetylcholinesterase inhibitors may delay their manifestation.