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.

阿尔茨海默病认知和病理学的性别差异建模 老年痴呆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AD，疾病的症状包括 认知障碍更严重。高胆固醇使这些性别差异进一步复杂化， 在中年，是AD的主要危险因素，并且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作用和胆固醇饮食相关性的认识还有很大的差距。 因为替代雌激素或用降胆固醇的他汀类药物治疗可能不会逆转 认知障碍，甚至会使情况变得更糟。我们建议模拟AD和AD的性别差异， 通过研究喂食胆固醇的雄性和雌性兔子， 在AD样病理和认知方面存在显著的性别差异。胆固醇喂养的女性发展β淀粉样蛋白 （Aβ）沉积比胆固醇喂养的男性更慢，卵巢切除术消除外周雌激素更多。 比Aβ水平加倍，表明雌激素对淀粉样病变的保护作用。我们有 初步数据表明，雌性高胆固醇喂养的兔子比雌性高胆固醇喂养的兔子更能记住眨眼的痕迹。 胆固醇饮食改变了雌激素受体α和β， 胆固醇代谢物27-羟基胆固醇（27-hydroxycholesterol，27-hydroxycholesterol，27-hydroxycholesterol）的血清和海马水平显著增加， 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， 初步数据表明，27-OHC升高的胆固醇喂养的兔子具有记忆缺陷。我们也有 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 在突触前活动区和突触后密度，雌性胆固醇喂养的兔子高于 男性。目前的研究重点是胆固醇诱导的27-OHC增加，具有直接的临床相关性 因为中年高胆固醇血症是AD的危险因素，重要的是，27-OHC显著升高， 轻度认知障碍和AD在两个具体的目标，我们将操纵雌激素（目标1）和雌激素 受体（目的2）在胆固醇喂养的兔子，以测试这一假设，即性别差异，在AD样认知 损伤和病理是内源性雌激素受体调节下游靶的功能。 利用行为学、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对内源性雌激素受体的调节机制 男性和女性的记忆、神经功能、胆固醇和Aβ加工标志物以及Aβ和tau水平 家兔我们在行为学、组织化学、电生理学和 在胆固醇喂养的兔子中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，使我们处于一个强有力的地位，对该领域产生重大影响。