Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD. Graphical Abstract Integrated model for the development of neuromuscular dysfunction in the AD-like pathology of 5xFAD mice. (A) At 3 mo of age, nerve-stimulated muscle function is normal across genotypes and sexes. (B) By as early as 4 mo of age, nerve-stimulated muscle function declines, and (C) corresponds to impaired sciatic nerve function in 5xFAD mice. Peripheral neuromuscular dysfunction (D) corresponds to an altered mitochondrial and transcriptional response of skeletal muscle to exercise training. (E) These peripheral phenotypes of the early AD-like pathology of 5xFAD mice were present in the absence of overt cognitive decline, particularly in male mice. Created in Biorender. [ABSTRACT FROM AUTHOR]