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

Bieri, Gregor; Pratt, Karishma J.B.; Fuseya, Yasuhiro; Aghayev, Turan; Sucharov, Juliana; Horowitz, Alana; Philp, Amber R.; Fonseca-Valencia, Karla; Chu, Rebecca; Phan, Mason; Remesal, Laura; Wang, Shih-Hsiu J.; Yang, Andrew C.; Casaletto, Kaitlin B.; Villeda, Saul

doi:10.1016/j.cell.2026.01.024

articleCellFeb 18, 2026HYBRID OA

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

GBGregor Bieri KJKarishma J.B. Pratt YFYasuhiro Fuseya TATuran Aghayev JSJuliana Sucharov

University of California, San Francisco · University of San Francisco · +4 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

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…

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Topics & keywords

Topics

Keywords

Cognition
Hippocampal formation
Cognitive decline
Mediator
Disease
Hippocampus
Phospholipase
Physical exercise

UN Sustainable Development Goals

Good health and well-being

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