Investigating the role of the exercise blood factor Gpld1 in restoring brain vasculature function and cognition in aging

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PROJECT SUMMARY Aging changes the adult brain at the molecular and cellular levels, driving cognitive impairments and drastically increasing susceptibility to neurodegenerative diseases, such as Alzheimer’s disease. Our lab, and others, have shown that broad systemic manipulations, such as heterochronic parabiosis, young blood plasma and exercise plasma administration can improve learning and memory cognitive functions in aged mice. Collectively, these findings raise the exciting possibility for systemic factors to restore brain function in aging with potential applications for degenerative conditions, including Alzheimer’s disease. Our lab recently described a liver-to- brain axis, in which administration of blood plasma derived from voluntary exercised mice exerts beneficial effects on the aged hippocampus, in part, through liver-derived circulating blood factors. In particular, we identified Glycosylphosphatidylinositol Specific Phospholipase D1 (Gpld1) – a plasma enzyme that cleaves GPI- anchored proteins (GPI-AP) from the cell surface – as an exercise-induced, liver-derived blood factor in aged mice and active elderly humans. Selectively increasing systemic Gpld1 was sufficient to restore learning and memory cognitive functions in the hippocampus of aged mice. While these exciting findings support a potential therapeutic role for systemic Gpld1 in aging, its cellular and molecular targets remain largely elusive. Surprisingly, our findings indicate that Gpld1 does not readily enter the brain, suggesting an indirect mechanism of action. Interestingly, GPI-APs are enriched on endothelial cells, raising the possibility that Gpld1 may be acting on the brain vasculature to improve cognition in the aged brain. Indeed, my preliminary data indicate that systemic Gpld1 restores expression of the GPI-anchored phosphatase ALPL, a regulator of vascular function, to more youthful levels on hippocampal blood vessels of aged mice. The purpose of this proposed study is to investigate the effect of systemic Gpld1 on the brain vasculature, as a critical mediator of its benefits on the aged brain. I hypothesize that targeting vascular GPI-anchored Gpld1 substrates ameliorates age-related vascular dysfunction and rejuvenates cognitive function in the aged hippocampus. This will be investigated with two Specific Aims: 1) Investigate the effects of increasing systemic Gpld1 on vascular dysfunction in the aged hippocampus. 2) Determine the rejuvenating potential of targeting the GPI-anchored Gpld1 substrate ALPL on cognitive function in the aged hippocampus. Ultimately, these studies will have significant translational potential, identifying molecular and cellular mechanisms downstream of Gpld1 as novel therapeutic targets to counter cognitive impairments in the aging brain and aging-associated neurodegenerative diseases, including Alzheimer’s disease.