LAUSR

INTRODUCTION Skeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through the secretion of skeletal muscle originating factors (‘myokines’) with neuroprotective properties. However, the precise mechanisms underlying these benefits in the context of Alzheimer’s disease (AD) remain poorly understood. METHODS To investigate muscle-to-brain axis signaling in response to amyloid β (Aβ)- induced toxicity, we generated 5xFAD transgenic female mice with enhanced skeletal muscle function (5xFAD;cTFEB;HSACre) at prodromal (4-months old) and late (8-months old) symptomatic stages. RESULTS Skeletal muscle TFEB overexpression reduced Aβ plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8- months-old 5xFAD mice. These changes were associated with transcriptional and protein remodeling of neurotrophic signaling and synaptic integrity, partially due to the CNS-targeting myokine prosaposin (PSAP). DISCUSSION Our findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.