LIVER EXERCISE FACTOR REVERSES AGING AND ALZHEIMER’S-RELATED MEMORY LOSS BY TARGETING BRAIN VASCULATURE

Blood factors transfer the benefits of exercise to the aged brain. However, mechanisms to restore cognition and the translational application to neurodegenerative disorders are unknown. Here we show that liver-derived exercise factor glycosylphosphatidylinositol (GPI)-specific phospholipase D1(Gpld1)–a GPI-degrading enzyme–reverses aging and Alzheimer’s-related memory loss by targeting brain vasculature. Increasing Gpld1 rejuvenated transcriptional hippocampal aging signatures at a single cell level and rescued memory in aged mice. Mechanistically, we identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on brain vasculature as a GPLD1 substrate. Mimicking an age-related increase in cerebrovascular TNAP impaired memory in young mice and mitigated Gpld1-mediated cognitive benefits in aged mice. Inhibiting TNAP activity recapitulated the benefits of Gpld1 in old age. In an Alzheimer’s disease model, increasing Gpld1, or inhibiting TNAP, ameliorated A pathology and improved cognitive deficits. Collectively, our data identify cerebrovasculature as a gatekeeper of the restorative cognitive benefits of a liver-to-brain exercise axis.