The Impact of Sex and Hippocampal Angiotensin II on Alzheimer's Disease

Abstract Alzheimer’s disease (AD) is the most common form of dementia in the aged population. An ongoing conundrum within the AD field is that despite women with dementia outnumbering men two to one, the efficacy of hormone replacement therapy appears to be limited. This suggests that the mechanism responsible for the increased risk of AD in women extends beyond direct hormone activity, wherein the neurobiological effects of sex hormones are dependent on other variables (e.g., angiotensin II). We and others have demonstrated that angiotensin II, a critical mediator of vasoconstriction, can amplify AD hallmarks in the brain, such as oxidative stress, amyloid plaques, and neurofibrillary tau tangles. We also discovered that the female sex chromosome XX is associated with increased angiotensin II activation compared to XY. Further, previous work has shown that androgens can upregulate angiotensin II signaling, whereas estrogens can downregulate angiotensin II signaling, alluding to a link between the sex hormones and angiotensin II activation. Notably, post-menopausal women have higher levels of androgens than estrogens and exhibit increased angiotensin II activity compared to aged men, which may explain their increased risk for developing AD. We hypothesize that cognitive impairment and increased AD risk in post-menopausal women is related to upregulated angiotensin II activation from XX sex chromosome and higher androgens levels due to loss of ovarian estradiol. We will test this hypothesis directly in aged male and female TgF344-AD rats and four core genotype (FCG) rats. We propose three specific aims 1) To determine the role of circulating hormones on modulating brain angiotensin II-associated oxidative stress and cognitive impairment, 2) To examine the role of brain-derived hormones on modulation of angiotensin II-associated oxidative stress and cognitive impairment, 3) To determine the independent effects of sex hormones and sex chromosomes on angiotensin II-associated oxidative stress and cognitive impairment. Our integrative approach will allow us to elucidate mechanisms involved in the observed sex differences in AD, in which post-menopausal women are at the highest risk for AD and cognitive decline. These proposed studies will be the first to examine the interaction between sex chromosomes, sex hormones, brain-derived hormones, and brain angiotensin II activation on accelerated brain aging and cognitive decline.