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, independent of physical activity. 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. GPLD1 has potential to cleave over 100 putative GPI-anchored proteins, necessitating identification of downstream targets that mediate cognitive rejuvenation for translational application. We identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on brain vasculature as a GPLD1 substrate. Mimicking the age-related increase in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice and mitigated Gpld1-induced cognitive benefits in aged mice. Inhibiting TNAP recapitulated 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 Ab pathology and improved cognitive deficits. We thus identify brain vasculature as a mediator of the cognitive benefits of a liver-to-brain exercise axis. Overall design: Hippocampal brain endothelial cells (BECs) isolated from young and aged control mice, aged mice with liver expression of GPLD1 and aged mice treated with a TNAP inhibitor (TNAPi) using fluorescence activated cell sorting (FACS). Pool of 8 mice/group.