Liver exerkine reverses aging- and Alzheimer's-related memory loss via vasculature
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 cogni
Content
# Liver exerkine reverses aging- and Alzheimer's-related memory loss via vasculature
*Published: 2026 Mar 5*
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.
DOI: 10.1016/j.cell.2026.01.024