Targeting angiotensin II in cognitive impairment associated with ovarian hormone loss

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Women who have undergone bilateral oophorectomy prior to natural menopause are at increased risk of developing dementia including Alzheimer's disease (AD) than age-matched women. There is a need for more therapeutic options to protect cognitive function. Bilateral oophorectomy before the onset of natural menopause causes an abrupt cessation of estrogen production with a consequent drop in circulating levels of estrogen (primarily 17-estradiol). Controversy, however, over the harm vs. benefit of estrogen replacement therapy (ERT) for cognition continues. Even if ERT is proven to provide cognitive benefits, ERT is contraindicated in some women and others may not elect ERT for other reasons. Targeting the renin angiotensin system offers a promising new therapeutic approach. Individuals with hypertension are at increased risk of age-associated cognitive decline and dementia including AD. Clinical studies with different classes of anti-hypertensive drugs have shown that effectiveness for protecting cognitive function varies independently of their effect on blood pressure (BP). Several clinical studies showed angiotensin type 1 receptor (AT1R) blockers (ARBs) to be superior to other antihypertensive drugs at reducing the risk of cognitive decline or dementia including AD. These clinical findings suggest that ARBs protect against cognitive decline and conversion to AD in both a BP-dependent and -independent manner. Studies in male animals support the clinical findings of ARBs exerting protective effects on cognition independently of their effects on BP and studies suggest AT1Rs are more active in AD; however, little is known regarding the cognitive protective effects of ARBs in women who are ovarian hormone deficient prior to the natural age of menopause and no basic science research has been published to date on the effects of ARBs on mechanisms of cognition in a female model of premenopausal ovarian hormone deficiency. In Aim 1, we will determine the role of age and estrogen loss on endothelial function in cerebral resistance arterioles and hippocampus neuropathology associated with AD in a model of hypertension and cognitive decline. In Aim 2, we will determine the role of neuronal AT1R activity and blood pressure on endothelial function in cerebral resistance vessels, hippocampus RAS activity and neuropathology and cognitive impairment as a function of ovariectomy. This research may inform the design of new therapeutics and intervention trials for women who undergo premenopausal bilateral oophorectomy as well as provide insights into protection of cognitive function for women who experience premature ovarian failure and post-menopausal women. 1