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bioRxiv · 10.1101/2024.06.14.599115

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

Taha, H. B.·Birnbaum, A.·Matthews, I.·Aceituno, K.·Leon, J.·Godoy-Lugo, J.·Thorwald, M. A.·Cortes, C. J.
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Abstract

INTRODUCTIONSkeletal 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 Alzheimers disease (AD) remain poorly understood. METHODSTo investigate muscle-to-brain axis signaling in response to amyloid {beta} (A{beta})- 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. RESULTSSkeletal muscle TFEB overexpression reduced A{beta} 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). DISCUSSIONOur findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.

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Taha, H. B., Birnbaum, A., Matthews, I., Aceituno, K., Leon, J., Godoy-Lugo, J., Thorwald, M. A., Cortes, C. J.. 2024-06-16. Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer disease mouse model via enhancing neurotrophic and synaptic signaling. https://doi.org/10.1101/2024.06.14.599115

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