PROJECT SUMMARY/ ABSTRACT Neurovascular dysfunction has been linked to Alzheimer’s disease (AD) evolution in experimental, imaging, pathological, and epidemiological studies. These key findings have led to an emerging ‘neurovascular hypothesis’ of AD, which holds that cerebrovascular dysfunction contributes to the onset and progression of cognitive decline. There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow (CBF) reductions and dysregulation, and breakdown of the blood-brain barrier (BBB), including the loss of pericytes, are early events in the AD pathophysiological cascade. Pericytes are mural cells on capillaries that are critical for the maintenance of the BBB, and have recently been implicated in the regulation of CBF. Importantly, pericytes deteriorate and the BBB degrades in AD. Based on our preliminary findings we hypothesize that pericytes are contractile cells that regulate capillary diameter and thereby CBF, and BBB integrity, and that this pericyte regulation is impaired in normal aging and in the presence of Aβ40 and Aβ42 via p75NTR pathway. To test this hypothesis, I will use cutting-edge approaches including in vivo two- photon/confocal brain vascular imaging to assess pericyte contractility, capillary diameter, CBF changes and BBB integrity. Brain tissue analysis will also be performed. I will determine if brain pericytes retain contractility, properly regulate CBF, and maintain BBB integrity in normal aging and in the presence of Aβ40 and Aβ42 (AIM 1/ K99). Also, I will determine if normal aging and Aβ40 and Aβ42 impair brain BBB integrity via p75NTR (AIM 2/ R00). Understanding how pericytes regulate CBF and BBB integrity in normal aging and AD and the involvement and potential of p75NTR as a therapeutic target for AD is timely and important. This K99/R00 grant is essential for my success in becoming an impactful tenure-track assistant professor because it provides me training in an essential technique to investigate neurovascular dynamics for future studies, and also will provide professional training in improving oral presentation and grant writing skills.