Tier 3 — preclinical

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

Hash Brown Taha, Allison Birnbaum, Ian Matthews, Karel Aceituno, Jocelyne Leon, Max Thorwald, Jose Godoy-Lugo, Constanza J. Cortes
GeroScience 2025 47:1593–1613

Bibliography

PubMed
PMID 39269584
PubMed Central
PMC11978596
DOI
10.1007/s11357-024-01345-3
Funding
SCELC open-access support; NIH R01 AG077536; NIA T32 AG052374; Alzheimer’s Association Research Fellowship AARF-21-851362
Competing interests
No competing interests declared.

Study snapshot

DesignPreclinical transgenic Alzheimer’s disease mouse study examining enhanced skeletal-muscle TFEB signaling and downstream brain effects.
ModelFemale 5xFAD Alzheimer’s disease mice with enhanced skeletal-muscle TFEB signaling, assessed at 4 and 8 months.
SampleMultiple mouse cohorts; n varied by experiment
InterventionSkeletal-muscle-specific TFEB overexpression in female 5xFAD mice
Duration4- and 8-month-old disease-stage cohorts
EndpointsAmyloid-beta plaque accumulation in cortex and hippocampus; Neurocognitive performance; Neurotrophic signaling; Synaptic signaling; Muscle-to-brain signaling including prosaposin-associated pathways

What the study showed, in plain terms

In female 5xFAD Alzheimer’s disease mice, increasing TFEB signaling specifically in skeletal muscle reduced amyloid-beta plaque burden in the cortex and hippocampus and improved neurocognitive deficits at the later disease stage. The study also identified remodeling of neurotrophic and synaptic signaling, including pathways involving prosaposin. It supports the muscle-to-brain TFEB concept in a mouse model but did not test PS18 or any human intervention.

Key findings

Skeletal-muscle TFEB enhancement reduced amyloid-beta pathology at both studied ages and rescued neurocognitive deficits at 8 months in female 5xFAD mice. Molecular analyses supported increased neurotrophic and synaptic signaling and a muscle-to-brain communication pathway that may partly involve prosaposin.

What this study can and cannot tell us

This is a transgenic mouse study in female 5xFAD animals. It did not test PS18, a supplement, or a human intervention. Genetic TFEB overexpression can differ materially from pharmacologic activation, and the disease model does not establish clinical efficacy in Alzheimer’s disease or healthy aging.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology