Modeling sex differences in Alzheimer's disease cognition and pathology

模拟阿尔茨海默病认知和病理学中的性别差异

• 批准号: 9893516
• 负责人: OTHMAN GHRIBI
• 金额: $ 59.43万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893516
• 关键词: 27-hydroxycholesterol; ATP binding cassette transporter 1; Affect; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Behavioral; Biological; Brain Pathology; Cholesterol; Cognition; DLG4 gene; Data; Dementia; Deposition; Diabetes Mellitus; Diet; Disease; Electrophysiology (science); Estradiol; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exhibits; Female; Genetic Transcription; Hippocampus (Brain); Hypertension; Impaired cognition; Incidence; Knowledge; Learning; Mediating; Membrane; Memory; Memory impairment; Menopause; Mitochondria; Modeling; Modification; Molecular; Nerve Degeneration; Neurons; Neurophysiology - biologic function; Obesity; Oryctolagus cuniculus; Ovariectomy; Pathology; Pathway interactions; Patients; Peripheral; Play; Positioning Attribute; Prefrontal Cortex; Prevalence; Property; Proteins; Research; Risk Factors; Role; Serum; Sex Differences; Signal Pathway; Symptoms; Synapses; Synaptic plasticity; Techniques; Testing; Woman; amyloid pathology; biological research; clinically relevant; cognitive performance; density; experimental study; eyeblink conditioning; feeding; hypercholesterolemia; indexing; male; men; middle age; mild cognitive impairment; neuroprotection; postsynaptic; presynaptic; protective effect; protein biomarkers; protein expression; receptor; tau Proteins; young adult

Abstract Modeling sex differences in Alzheimer’s Disease cognition and pathology There are significant differences between men and women in the incidence and prevalence of Alzheimer’s Disease (AD). After menopause, women are more likely to develop AD, and symptoms of the disease including cognitive impairment are more severe. These sex differences are further complicated by high cholesterol which, at midlife, is a major risk factor for AD, and there is substantial interaction between estrogen and cholesterol. There is a significant gap in our knowledge of how estrogen neuroprotection and cholesterol diet-associated vulnerability converge because replacing estrogen or treating with cholesterol-lowering statins may not reverse cognitive impairment and can even make it worse. We propose to model sex differences in AD and the complicating effects of high cholesterol by studying cholesterol-fed male and female rabbits because they show significant sex differences in AD-like pathology and cognition. Cholesterol-fed females 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 against amyloid pathology. We have preliminary data suggesting female cholesterol-fed rabbits remember trace eyeblink conditioning better than cholesterol-fed males and that a cholesterol diet alters estrogen receptors alpha and beta which correlates with a significant increase in serum and hippocampal levels of the cholesterol metabolite, 27-hydroxycholesterol (27- OHC). 27-OHC is an endogenous estrogen receptor modulator that may play a role in learning and memory because patients with mild cognitive impairment (MCI) and AD exhibit elevated 27-OHC levels and we have preliminary data suggesting cholesterol-fed rabbits with elevated 27-OHC have memory deficits. We also have new data showing 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 males. The present research focus on cholesterol-induced increases in 27-OHC has direct clinical relevance because midlife hypercholesterolemia is a risk factor for AD and, importantly, 27-OHC is significantly elevated in mild cognitive impairment and AD. In two specific aims, we will manipulate estrogen (Aim 1) and estrogen receptors (Aim 2) in cholesterol-fed rabbits to test the hypothesis that sex differences in AD-like cognitive impairment and pathology are a function of endogenous estrogen receptor modulation of downstream targets. Using behavioral, electrophysiological, histochemical and molecular biological techniques, we will determine the mechanisms by which endogenous estrogen receptor modulation by cholesterol diet-induced 27-OHC affects memory, neural function, markers of cholesterol and Aβ processing, and Aβ and tau levels in male and female rabbits. Our combined expertise in and track record of behavioral, histochemical, electrophysiological and molecular biological research in cholesterol-fed rabbits makes us a particularly well-suited collaborative team to conduct these experiments and places us in a strong position to have a significant impact on the field.

阿尔茨海默病认知与病理性别差异模型的建立 阿尔茨海默氏症的发病率和患病率在男性和女性之间存在显著差异 疾病(AD)。绝经后，女性更容易患上阿尔茨海默病，这种疾病的症状包括 认知障碍更为严重。这些性别差异因高胆固醇而进一步复杂化， 在中年，雌激素是阿尔茨海默病的主要风险因素，雌激素和胆固醇之间存在实质性的相互作用。 我们对雌激素、神经保护和胆固醇饮食之间的关系的了解存在很大差距。 脆弱性趋同，因为替代雌激素或使用降胆固醇的他汀类药物可能不会逆转 认知障碍，甚至会使情况变得更糟。我们建议建立AD的性别差异模型 通过研究高胆固醇喂养的雄性和雌性兔子使高胆固醇的影响复杂化，因为它们表明 在类AD的病理和认知方面存在显著的性别差异。摄入胆固醇的女性会患上β淀粉样蛋白 (aβ)比胆固醇喂养的男性沉积更慢，通过卵巢切除更多地消除外周雌激素 比Aβ水平翻了一番，表明雌激素对淀粉样蛋白病理具有保护作用。我们有 初步数据显示，喂饲胆固醇的雌性兔子对眨眼痕迹的记忆力好于 高胆固醇饮食会改变雌激素受体α和β，而雌激素受体与 血清和海马体中胆固醇代谢产物27-羟基胆固醇(27-羟基胆固醇)水平显著升高。 OHC)。27-OHC是一种内源性雌激素受体调节剂，可能在学习和记忆中发挥作用 因为轻度认知障碍(MCI)和AD患者表现出27-OHC水平升高，我们有 初步数据显示，27-OHC升高的高胆固醇喂养兔存在记忆缺陷。我们还有 雌激素受体转录活性和蛋白质表达性别差异的新数据 在雌性高胆固醇饮食兔的突触前活动区和突触后密度高于 男性。目前的研究集中在胆固醇诱导的27-OHC的增加上，这与临床直接相关。 因为中年高胆固醇血症是AD的危险因素，更重要的是，27-OHC显著升高 轻度认知障碍和阿尔茨海默病。在两个特定的目标中，我们将操纵雌激素(目标1)和雌激素 胆固醇喂养的兔的受体(Aim 2)来验证性别差异在类AD认知中的假设 损伤和病理是内源性雌激素受体调节下游靶点的功能。 利用行为、电生理、组织化学和分子生物学技术，我们将确定 高脂饮食诱导的27-OHC内源性雌激素受体调节机制的研究 男性和女性的记忆、神经功能、胆固醇和Aβ加工的标志物以及Aβ和Tau水平 兔子。我们在行为、组织化学、电生理和 对胆固醇喂养的兔子进行的分子生物学研究使我们成为一个特别适合合作的团队 进行这些实验，使我们处于有利地位，能够在该领域产生重大影响。