Neurovascular Changes During Midlife Hypertension and Alzheimer’s Disease

Project Summary

We will induce hypertension through infusion of angiotensin II (ATII) (Aim 1) and block ATII-induced hypertension through the use of an ATII type 1 receptor antagonist, telmisartan (Aim 2). To study the neurovascular and pathological changes in Alzheimer’s disease, we will employ microscopic techniques to study cerebrovascular structure, blood-brain barrier breakdown, amyloid-beta deposition, and neuroinflammation, advanced widefield optical imaging to study resting-state cerebral blood flow and neurovascular coupling, and perform cognitive testing in the well-established Tg2576 model. 

This work is innovative because it will employ multiscale approaches to investigate the longitudinal impact of angiotensin II (ATII)-induced hypertension during midlife on structural and functional changes to the blood-brain barrier (BBB), cerebral blood flow, and Alzheimer’s disease (AD) progression. Furthermore, BBB-crossing angiotensin receptor blockers (ARBs), such as telmisartan, are shown to slow cognitive decline. This research will study the effects of telmisartan, which is currently in phase 1 and 2 clinical trials for AD, on neurovascular alterations during AD. Upon completion of this study, the general public can benefit from results that determine if commonly prescribed blood-brain barrier (BBB) crossing angiotensin receptor blockers (ARBs) improve cognition, slow Alzheimer’s disease pathogenesis, and preserve neurovascular changes during midlife hypertension. From a research perspective, more clinically translatable studies from midlife into late-life can be designed to help determine therapeutic time windows that rescue cognitive decline and ameliorate vascular and Alzheimer’s disease pathological alterations.