Liver exerkine reverses aging- and Alzheimer's-related memory loss via vasculature.

GPLD1, a liver-derived exercise factor, reverses aging-related memory loss by targeting brain vasculature.

• GPLD1 is a GPI-degrading enzyme classified as a liver-derived exerkine.
• GPLD1 has the potential to cleave over 100 putative GPI-anchored proteins.
• Blood factors transfer the benefits of exercise to the aged brain independent of physical activity.
• Brain vasculature was identified as the primary mediator of GPLD1's cognitive benefits.

GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on the brain vasculature was identified as a downstream substrate of GPLD1.

• TNAP is a GPI-anchored protein expressed on the cerebrovascular endothelium.
• GPLD1 cleaves TNAP as part of its GPI-degrading enzymatic activity.
• Identification of TNAP as a substrate was necessary to pinpoint the mechanism of cognitive rejuvenation for translational application.

Mimicking age-related increases in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice.

• Experimentally increasing TNAP levels in young mice reproduced age-associated cognitive deficits.
• Elevated cerebrovascular TNAP was associated with impaired blood-brain transport.
• This manipulation also mitigated GPLD1-induced cognitive benefits in aged mice.

Inhibiting TNAP recapitulated the cognitive benefits of GPLD1 in aged mice and restored youthful hippocampal transcriptional signatures.

• Pharmacological or genetic inhibition of TNAP was sufficient to rescue cognition in old age.
• TNAP inhibition restored hippocampal transcriptional signatures to a more youthful state.
• These effects paralleled those observed with GPLD1 overexpression or exercise-induced GPLD1 elevation.

In an Alzheimer's disease mouse model, increasing GPLD1 or inhibiting TNAP ameliorated amyloid-beta pathology and improved cognitive deficits.

• Both GPLD1 elevation and TNAP inhibition were tested in an Alzheimer's disease model.
• Treatment reduced Aβ pathology in the Alzheimer's disease model.
• Cognitive deficits were improved by both interventions targeting the GPLD1-TNAP axis.
• Findings extend the relevance of this liver-to-brain exercise axis beyond normal aging to Alzheimer's disease.

The study identifies a liver-to-brain exercise axis mediated by brain vasculature as the mechanism by which exercise-induced GPLD1 confers cognitive benefits.

• GPLD1 is secreted by the liver in response to exercise.
• The vascular target TNAP serves as a functional link between systemic GPLD1 and hippocampal cognitive function.
• This axis operates independent of direct physical activity, as blood-borne factors alone are sufficient to transfer cognitive benefits.