Neurovascular Changes During Midlife Hypertension and Alzheimer’s Disease

Summary

The goal of this project is to study the structural and functional neurovascular changes during the progression of Alzheimer’s disease and how hypertension alters these dynamics throughout midlife.

Project Details

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.