Impact of sex differences on molecular determinants of AD risk and responsiveness to treatment

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ABSTRACT: There are significant differences between men and women in the incidence and severity of late- onset Alzheimer’s Disease (LOAD). After menopause, women are more likely to develop LOAD, and symptoms of the disease including cognitive impairment are more severe. These symptoms are exacerbated by high cholesterol which, at midlife, is a major risk factor for LOAD. There is a substantial gap in our knowledge of how estrogen and cholesterol interact. We propose to examine the role of estrogen and cholesterol in LOAD sex differences by studying male and female cholesterol-fed rabbits – an unconventional but promising model of LOAD. These rabbits show significant sex differences in AD-like pathology, estrogen receptor transcriptional activity and protein expression, and differences in cognition. Cholesterol-fed female rabbits develop beta amyloid (Aβ) deposits more slowly than cholesterol-fed males and eliminating peripheral estrogen by ovariectomy more than doubles Aβ levels, suggesting a protective role for estrogen. We have evidence that a cholesterol diet alters estrogen receptors, significantly increases serum and hippocampal levels of the cholesterol metabolite, 27-hydroxycholesterol (27-OHC), and female cholesterol-fed rabbits remember hippocampally-dependent learning better than cholesterol-fed males. 27-OHC is a well-documented endogenous selective estrogen receptor modulator that may play a role in learning and memory because patients with mild cognitive impairment (MCI) and AD show elevated 27-OHC levels and we have evidence that cholesterol-fed rabbits have elevated 27-OHC and memory deficits. We also have data showing there are sex differences in the transcriptional activity of estrogen receptors and expression of proteins in the presynaptic active zone and postsynaptic density that are higher in female cholesterol-fed rabbits than in males. Our research focus on cholesterol-induced increases in 27-OHC has direct clinical relevance because midlife hypercholesterolemia is a significant risk factor for LOAD and, as noted, 27-OHC is elevated in MCI and LOAD. In three specific aims, we will manipulate estrogen (Aim 1), 27-OHC (Aim 2), and estrogen receptors (Aim 3) in cholesterol-fed rabbits to test the hypothesis that sex differences in AD-like cognitive impairment and pathology are a function of estrogen and can be rescued with estrogen receptor modulation. Using behavioral, electrophysiological, histochemical, and molecular biological techniques, we will determine the mechanisms by which estrogen receptor modulation affects memory, neural function, markers of cholesterol and Aβ processing, and Aβ and tau levels in intact and castrated male and in intact and ovariectomized female cholesterol-fed rabbits. Our expertise in and track record of behavioral, histochemical, electrophysiological, and molecular biological research in cholesterol-fed rabbits makes us a particularly well-suited team to conduct these experiments, further validate this non-transgenic model of LOAD, and positions us to help understand the impact of sex differences on the molecular determinants of LOAD risk and responsiveness to treatment.