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

Abstract

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.

Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function

“…Overexpression of mutant tau in skeletal muscle could be an unintentional consequence of tauopathy models under the mouse prion promoter [23] , [24] , [29] . In the AAV8-P301L model, in vivo weakness is observed prior to reported cognitive deficits of the model, which aligns with the reduction in plantar flexor torque production in the 5xFAD model prior to cognitive decline and the clinical increased risk for dementia in humans with low handgrip strength [17] , [30] , [31] , [32] , [33] , [34] . Furthermore, human tau overexpression is not detected in muscle tissue and ex vivo muscle contractile weakness was detected with a measurement that is independent of motor neuron signaling ( Fig.…”

“…This finding supports that tauopathy has peripheral consequences beyond gene expression that have detrimental outcomes to skeletal muscle funciton. Recently, reduced plantar flexor torque in the 5xFAD model was revealed by tibial nerve stimulation but not direct muscle stimulation [34] . We show that in skeletal muscle alone, independent of nerve stimulation, force production is blunted in the AAV8-P301L model.…”