Leveraging mouse and human models to investigate neuroprotective effects of blood-derived exerkines in Alzheimer's disease

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ABSTRACT Alzheimer’s disease (AD) is an untreatable, precipitously growing public health problem. Continued failed and equivocal trials for amyloid lowering drugs highlight the urgent need for alternative solutions to support the aging brain and prevent AD. Physical activity is a readily available therapy associated with >30% reduced risk of Alzheimer’s dementia; yet, how physical activity, a putatively systemic intervention, promotes brain health is not fundamentally understood. Capturing the neurologically active mechanisms of physical activity offers an opportunity to identify novel AD treatment targets and refine our understanding of one of the most widely implemented behavioral interventions for brain health. This proposal builds on a recent collaboration between Drs. Villeda and Casaletto that culminated in a publication in Science in which their teams identified a novel blood factor, Glycosylphosphatidylinositol-Specific Phospholipase D1 (Gpld1), that mediates the neurogenic and memory benefits of exercise in aged mice and relates to physical activity levels in humans. Gpld1 is a liver- derived enzyme that cleaves GPI-anchored proteins from the cell surface, thereby regulating GPI-anchored protein cascades. We observed that Gpld1 does not readily enter the brain parenchyma, suggesting an indirect mode of action. Our preliminary mouse and human data suggest that systemic Gpld1 lowers complement and coagulation activation, regulates GPI-anchored proteins on hippocampal blood vessels, and relates to lower plasma complement activation and better MRI markers of cerebrovascular integrity in healthy older adults. Together, this suggests that Gpld1 acts on immunovascular processes to support brain health. Given the early and predominant involvement of immunovascular dysfunction in AD, we now plan to examine the neuroprotective effects of plasma Gpld1 in AD using a cross-species design. We hypothesize that, through immunovascular mechanisms, Gpld1 may ameliorate the neurotoxicity and propagation of AD pathology, resulting in slower pathology accumulation and improved cognition in AD. In our Aims, we will: 1) test the longitudinal relationships between plasma Gpld1 with physical activity monitoring (actigraphy), immunovascular, and cognitive trajectories in 150 older adults across the AD continuum; 2) test the effect of systemic Gpld1 modulation on immunovascular and neurodegenerative outcomes in a mouse model of AD pathology; and 3) characterize a vascular GPI- anchored Gpld1 substrate, tissue nonspecific alkaline phosphatase (TNAP/ALPL), that has been shown to negatively regulate blood-brain transport and be increased and inversely correlate with cognition in AD adults. Our project is positioned to identify the utility of a novel AD therapy target that will be simultaneously tested for causal pathways in rodent models of AD pathology and evaluated for clinical relevance in humans. Longer term, this proposal will both facilitate our foundational understanding of how physical activity impacts brain health, and set the stage for a potential novel clinical trial for AD.