Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling

Author:

Taha Hash Brown,Birnbaum Allison,Matthews Ian,Aceituno Karel,Leon Jocelyne,Thorwald Max,Godoy-Lugo Jose,Cortes Constanza J.

Abstract

AbstractSkeletal 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. 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. Skeletal muscle TFEB overexpression reduced Aβ plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8-month-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). Our findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.

Funder

National Institute on Aging

Alzheimer's Association

University of Southern California

Publisher

Springer Science and Business Media LLC

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