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: 9914168
• 负责人: OTHMAN GHRIBI
• 金额: $ 58.13万
• 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 2021-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914168
• 关键词: 27-hydroxycholesterol; ATP binding cassette transporter 1; Affect; Age; Agonist; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease pathology; 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; 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.

摘要：模拟阿尔茨海默病认知和病理学中的性别差异 男性和女性阿尔茨海默病的发病率和患病率存在​​显着差异 疾病（AD）。绝经后，女性更容易患 AD，该疾病的症状包括 认知障碍更为严重。高胆固醇使这些性别差异变得更加复杂， 中年时期是 AD 的主要危险因素，雌激素和胆固醇之间存在显着的相互作用。 我们对雌激素神经保护作用和胆固醇饮食如何相关的了解存在很大差距 由于替代雌激素或用降胆固醇他汀类药物治疗可能无法逆转，脆弱性趋于一致 认知障碍，甚至会使情况变得更糟。我们建议对 AD 中的性别差异进行建模 通过研究用胆固醇喂养的雄性和雌性兔子，使高胆固醇的影响变得复杂化，因为它们表明 AD 样病理学和认知方面存在显着的性别差异。吃胆固醇的女性会产生β淀粉样蛋白 (Aβ) 沉积速度比胆固醇喂养的男性更慢，并且通过卵巢切除术消除外周雌激素更多 Aβ 水平增加一倍以上，表明雌激素对淀粉样蛋白病理具有保护作用。我们有 初步数据表明，用胆固醇喂养的雌性兔子比兔子更能记住微量眨眼条件反射。 以胆固醇喂养的男性，胆固醇饮食会改变雌激素受体α和β，这与 胆固醇代谢物 27-羟基胆固醇 (27- 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 患者的 27-OHC 水平升高，我们有 初步数据表明，用胆固醇喂养且 27-OHC 升高的兔子存在记忆缺陷。我们还有 新数据显示雌激素受体转录活性和蛋白质表达的性别差异 雌性胆固醇喂养兔子的突触前活性区和突触后密度高于雌性兔子 男性。目前的研究重点是胆固醇引起的 27-OHC 增加，具有直接的临床意义 因为中年高胆固醇血症是 AD 的危险因素，而且重要的是，27-OHC 显着升高 轻度认知障碍和 AD。在两个具体目标中，我们将操纵雌激素（目标 1）和雌激素 受体（目标 2）在胆固醇喂养的兔子中，以检验 AD 样认知中性别差异的假设 损伤和病理学是下游靶标的内源性雌激素受体调节的函数。 使用行为、电生理学、组织化学和分子生物学技术，我们将确定 胆固醇饮食诱导的 27-OHC 影响内源性雌激素受体调节的机制 男性和女性的记忆、神经功能、胆固醇和 Aβ 加工标记物以及 Aβ 和 tau 蛋白水平 兔子。我们在行为、组织化学、电生理学和 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的合作团队 进行这些实验并使我们处于对该领域产生重大影响的有利地位。