Diversity Supplement (Qudrat Abdulwahab) for Role of pericyte nanotubes in age-related neurovascular dysfunction

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PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease associated dementias are characterized by marked alterations in neural function and associated cognitive decline. Though changes to neurons themselves are important, recent findings by our group and others suggest another major contributor to pathogenesis: alterations to neurovascular coupling. In Alzheimer’s disease, signaling between neurons and vessels appears to break down, accompanied by defects in vessel responses, cerebral amyloid angiopathy, and structural vascular alterations. However, little is known about the cellular or molecular basis of these changes. In this proposal, we identify a key mechanism responsible for maintaining vessel integrity in the context of aging and Alzheimer’s using the superbly tractable murine retina. We have shown that different retina neuron types exhibit distinct age- and Alzheimer’s disease-related dystrophies, and that dopaminergic neurons are a central target. In parallel, our data now reveal that neural changes are accompanied by distinct vascular dystrophies, with particular disruption to pericytes and their novel nanotube-like processes. Further, using genetic and pharmacological methods we and others have shown that dopamine can directly influence vascular organization and function and signal to pericytes. These data suggest that Alzheimer’s disease alters neuro- vascular coupling via declines in dopamine driven pericyte structure and function. In Aim 1, we determine how Alzheimer’s disease regulates vasculature structure and function, with a particular focus on pericytes. We test the hypothesis that pericyte alterations are accompanied by functional declines in vascular hemodynamics, loss of coupling nanotubes, and locally associated neural decline. In Aim 2, we examine the neural signaling defects causal to vascular structure and functional declines. Our preliminary data suggest that dopaminergic neurons are reduced in Alzheimer’s disease, and that dopamine is required for maintaining vessel integrity. We thus test the idea that declines in dopamine signaling are causal to vasculature dysfunction in Alzheimer’s disease and can be targeted to mitigate vascular pathology. These studies will lead to the identification of molecular pathways that drive neurovascular dysfunction in Alzheimer’s disease that may ultimately be useful for preventing pathogenesis.