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

性别差异对 AD 风险分子决定因素和治疗反应的影响

• 批准号: 10652594
• 负责人: Colin K Combs
• 金额: $ 59.8万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652594
• 关键词: 27-hydroxycholesterol; ATP binding cassette transporter 1; Adult; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Behavioral; Biological; Brain Pathology; Cholesterol; Clinical Trials; Cognition; Data; Dementia; Deposition; Diabetes Mellitus; Diet; Disease; ESR1 gene; Electrophysiology (science); Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Female; GPER gene; Genes; Genetic Transcription; Hippocampus; Hypertension; Impaired cognition; Incidence; Infusion procedures; Knowledge; Late Onset Alzheimer Disease; Learning; Male Castration; Measures; Membrane; Memory; Memory impairment; Mitochondria; Modeling; Molecular; Nerve Degeneration; Neuronal Plasticity; Neurophysiology - biologic function; Non-Rodent Model; Obesity; Oryctolagus cuniculus; Ovariectomy; Pathology; Pathway interactions; Patients; Peripheral; Positioning Attribute; Postmenopause; Prefrontal Cortex; Property; Proteins; Research; Risk; Risk Factors; Role; Selective Estrogen Receptor Modulators; Serum; Severities; Sex Differences; Signal Pathway; Symptoms; Synapses; Synaptic plasticity; Techniques; Testing; Transgenic Mice; Woman; anastrozole; beta amyloid pathology; biological research; clinically relevant; cognitive performance; density; dietary; experimental study; human old age (65+); hypercholesterolemia; improved; indexing; inhibitor; male; member; men; middle age; mild cognitive impairment; mouse model; neuroprotection; postsynaptic; postsynaptic density protein; presynaptic; programs; protein expression; tau Proteins; young adult

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.

摘要：男性和女性在事件中存在显着差异，而后期的严重程度 阿尔茨海默氏病（负载）。更年期后，女性更有可能发展负载和符号 包括认知障碍在内的疾病更严重。这些符号因高而加剧 胆固醇在中年是负载的主要危险因素。我们的了解如何 雌激素和胆固醇相互作用。我们建议检查雌激素和胆固醇在荷载性别中的作用 通过研究雄性和女性胆固醇喂养的兔子的差异 - 一种非常规但有希望的模型 加载。这些兔子在雌激素受体转录中显示出明显的性别差异 活性和蛋白质表达以及认知差异。胆固醇喂养的雌性兔子发展β 淀粉样蛋白（Aβ）的沉积比胆固醇喂养的雄性更慢，并消除了外周雌激素 卵巢切除术倍增Aβ水平，这表明雌激素的作用受到保护。我们有证据表明 胆固醇饮食改变雌激素受体，显着增加血清和海马水平 胆固醇代谢物，27-羟基胆固醇（27-OHC）和雌性胆固醇喂养的兔子记住 比胆固醇喂的男性更好地依赖海马。 27-OHC是有据可查的 内源性选择性雌激素受体调节剂可能在学习和记忆中起作用，因为患者 轻度认知障碍（MCI）和广告显示27-OHC水平升高，我们有证据表明 胆固醇喂养的兔子升高了27-OHC，记忆定义。我们也有数据显示有性别 雌激素受体的转录活性的差异和突触前蛋白的表达 雌性胆固醇喂养的兔子的活性区和突触后密度高于男性。我们的 研究重点是胆固醇诱导的27-OHC的增加具有直接的临床相关性，因为中年 高胆固醇血症是负载的重要危险因素，如前所述，MCI和负载中的27-OHC升高。 在三个特定目标中，我们将操纵雌激素（AIM 1），27-OHC（AIM 2）和雌激素受体（AIM 3） 胆固醇喂养的兔子以检验以下假设：广告样认知障碍和病理学上的性别差异 是雌激素的函数，可以通过雌激素受体调节来检索。使用行为， 电生理，组织化学和分子生物学技术，我们将通过 雌激素受体调节会影响记忆，神经功能，胆固醇和Aβ加工的标记， 以及完整和cast割男性的Aβ和Tau水平以及完整和卵巢胆固醇的胆固醇喂养 兔子。我们在行为，组织化学，电生理和分子方面的专业知识和跟踪记录 胆固醇喂养的兔子的生物学研究使我们成为一支特别适合进行这些团队 实验，进一步验证这种非转基因载荷模型，并为我们定位以帮助了解影响 负载风险和对治疗反应的分子决定剂的性别差异。