Publications

Dernière publication 18/02/2026

Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculatu

Summary Blood factors transfer the benefits of exercise to the aged brain independent of physical activity. Here, we show that the liver-derived...

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    [title] => Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculatu
    [paragraph] => Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature
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Authors
Gregor Bieri, Karishma J.B. Pratt, Yasuhiro Fuseya, Turan Aghayev, Juliana Sucharov, Alana M. Horowitz, Amber R. Philp, Karla Fonseca-Valencia, Rebecca Chu, Mason Phan, Laura Remesal, Shih-Hsiu J. Wang, Andrew C. Yang, Kaitlin B. Casaletto, Saul A. Villeda

 Lab

Journal
Cell
Abstract
Summary
Blood factors transfer the benefits of exercise to the aged brain independent of physical activity. Here, we show that the liver-derived exercise factor (exerkine) glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (GPLD1), a GPI-degrading enzyme, reverses aging- and Alzheimer's-related memory loss by targeting the brain vasculature. GPLD1 has the potential to cleave over 100 putative GPI-anchored proteins, necessitating the identification of downstream targets that mediate cognitive rejuvenation for translational application. We identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on the brain vasculature as a GPLD1 substrate. Mimicking age-related increases in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice and mitigated GPLD1-induced cognitive benefits in aged mice. Inhibiting TNAP recapitulated the benefits of GPLD1 in old age, restoring youthful hippocampal transcriptional signatures and rescuing cognition. In an Alzheimer's disease model, increasing GPLD1 or inhibiting TNAP ameliorated Aβ pathology and improved cognitive deficits. We thus identify brain vasculature as a mediator of the cognitive benefits of a liver-to-brain exercise axis.

Keywords/Topics
aging; rejuvenation; Alzheimer’s disease; exercise; GPLD1; liver; vasculature; blood-brain barrier; blood factors; cognition
BIOSEB Instruments Used:
Grip strength test (BIO-GS4)
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Une méthode simple pour quantifier objectivement la force musculaire des rats et souris et l'effet de drogues, toxines, maladies musculaires (ex: myopathie) et neurodégénératives. Cette mesure de force est souvent employée en association avec le test de coordination motrice ROTAROD: un sujet présentant une coordination normale montrera des résultats médiocres en cas de faible force musculaire. Un must pour vos recherches sur l'activité, la coordination et le contrôle musculaire: particulièrement utile pour vos études sur les maladies de Parkinson et Huntington.
Nouveautés GS4 - 2023: Écran couleur rétroéclairé (meilleure lisibilité), pédale de remise à zéro, durée de batterie optimisée, taille de mémoire augmentée à 500 valeurs, compteur d'animaux, port USB (transfert de données/charge)

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