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

• Liver exercise factor GPLD1 targets GPI-anchored proteins on the aged brain vasculature • GPI-anchored TNAP on brain endothelial cells disrupts the BBB and impairs cognition • Increased GPLD1 or TNAP inhibition rejuvenates BBB function and cognition in aging • Increased GPLD1 or TNAP inhibition ameliorates Alzheimer’s disease pathology Liver exercise factor GPLD1 targets GPI-anchored proteins on the aged brain vasculature GPI-anchored TNAP on brain endothelial cells disrupts the BBB and impairs cognition Increased GPLD1 or TNAP inhibition rejuvenates BBB function and cognition in aging Increased GPLD1 or TNAP inhibition ameliorates Alzheimer’s disease pathology 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.