Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature
TL;DR
This discovery could lead to new treatments for age-related memory loss and Alzheimer's disease that don't require physical exercise. Instead of just telling people to exercise more, doctors might eventually be able to give patients the specific liver protein (GPLD1) or drugs that block TNAP to achieve the brain benefits of exercise. This is especially important for elderly or disabled people who cannot exercise regularly but still want to protect their memory and cognitive function.
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.
- 1Exercise triggers the liver to release GPLD1, a protein that can improve memory and cognition without requiring physical activity
- 2GPLD1 works by targeting a specific protein called TNAP on brain blood vessels that becomes problematic with age
- 3When TNAP levels increase with aging, it impairs the blood-brain barrier and hurts memory function
- 4Both increasing GPLD1 and directly blocking TNAP can restore youthful brain gene activity and rescue memory in aged mice
- 5In Alzheimer's disease models, this liver-to-brain pathway reduced harmful protein buildup and improved cognitive problems
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