Project 3 Summary An unresolved and important question is whether estrogen’s protective effects on the brain and cognition are attenuated or reversed during diseases such as hypertension. The goal of our overall Program Project is to address this critical gap using preclinical rodent models of healthy and unhealthy aging to understand estrogen’s impact on female cognitive aging. The experiments proposed in Project 3 contribute to this goal by comparing the impact of estrogen on vascular health in models of healthy versus unhealthy aging and complement the other Research Projects in both concept and approach. Our overall hypothesis is that cardiovascular disease alters the estrogen receptor profile, disrupting the integration of estrogen’s molecular signaling pathways and attenuating estrogen’s cardiovascular effects and downstream protection from Alzheimer’s disease and vascular dementia. Aim 1 will determine the impact of cardiovascular disease on the vascular response to hormone therapy. This aim utilizes the same middle-aged Long-Evans rat model of postmenopausal hypertension and cognitive decline as Project 1 led by Dr. Jill Daniel and builds upon our previous co-authored publication. Aim 2 will establish whether altered estrogen receptor expression impacts the response to estrogen. These experiments utilize transgenic ERE-luciferase mice along with mice lacking either ERα or GPER to grasp how cardiovascular disease alters each of these signaling pathways to reduce estrogen’s protective effects. Aim 3 will assess the impact of hypertension versus arterial stiffness on female cognition, dendritic plasticity, and neurovascular coupling and determine which antihypertensive provides the greatest protection to the brain. This aim was designed in collaboration with Co- Investigator Dr. Ricardo Mostany and utilizes his Thy-1 mouse line to directly assess central mechanisms that are associated with cognitive decline. The successful completion of the aims proposed in Project 3 will address critical gaps in our knowledge on the impact of menopausal hormone therapy, enable the development of novel methods for early detection and prevention of cardiovascular disease-induced cognitive decline, and provide innovative strategies for improving menopausal hormone pharmacology to protect from Alzheimer’s disease and vascular dementia.