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: 10295254
• 负责人: Colin K Combs
• 金额: $ 61.1万
• 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/10295254
• 关键词: 27-hydroxycholesterol; ATP binding cassette transporter 1; 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; Genetic Transcription; Hippocampus (Brain); Hypertension; Impaired cognition; Incidence; Infusion procedures; Knowledge; Late Onset Alzheimer Disease; Learning; Measures; Membrane; Memory; Memory impairment; Menopause; Mitochondria; Modeling; Molecular; Nerve Degeneration; Neurons; Neurophysiology - biologic function; Non-Rodent Model; Obesity; Oryctolagus cuniculus; Ovariectomy; Pathology; Pathway interactions; Patients; Peripheral; Play; Positioning Attribute; 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; base; biological research; clinically relevant; cognitive performance; density; dietary; experimental study; human old age (65+); hypercholesterolemia; improved; indexing; inhibitor/antagonist; male; men; middle age; mild cognitive impairment; mouse model; neuroprotection; postsynaptic; postsynaptic density protein; presynaptic; programs; protein biomarkers; 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：男性和女性之间在晚期乳腺癌的发生率和严重程度方面存在显著差异。 阿尔茨海默病（LOAD）。绝经后，女性更容易发展LOAD，症状 包括认知障碍在内的疾病更加严重。这些症状是由高 胆固醇，在中年，这是一个主要的危险因素负荷。我们对如何做到这一点 雌激素和胆固醇相互作用。我们建议研究雌激素和胆固醇在LOAD性行为中的作用 通过研究雄性和雌性胆固醇喂养的兔子-一种非传统但有前途的模型， 即可.这些兔在AD样病理学、雌激素受体转录水平、雌激素受体表达水平、雌激素受体表达水平、雌激素 活性和蛋白质表达，以及认知差异。胆固醇喂养的雌兔产生β 淀粉样蛋白（Aβ）的沉积速度比胆固醇喂养的男性慢， 卵巢切除术使Aβ水平增加一倍多，表明雌激素具有保护作用。我们有证据表明 胆固醇饮食改变了雌激素受体，显著增加了血清和海马的水平， 胆固醇代谢产物27-羟基胆固醇（27-OHC）和雌性胆固醇喂养的兔子记得 与胆固醇喂养的男性相比，依赖性学习更好。27-OHC是一个有据可查的 内源性选择性雌激素受体调节剂，可能在学习和记忆中发挥作用，因为患者 轻度认知障碍（MCI）和AD患者的27-OHC水平升高，我们有证据表明， 胆固醇喂养的兔子具有升高的27-OHC和记忆缺陷。我们也有数据显示 突触前雌激素受体转录活性和蛋白质表达的差异 活动区和突触后密度，雌性胆固醇喂养兔高于雄性。我们 研究重点是胆固醇诱导的27-OHC增加具有直接的临床意义， 高胆固醇血症是LOAD的重要危险因素，并且如所指出的，27-OHC在MCI和LOAD中升高。 在三个具体的目标中，我们将操纵雌激素（目标1），27-OHC（目标2）和雌激素受体（目标3）。 胆固醇喂养的兔子，以检验AD样认知障碍和病理学的性别差异的假设， 是雌激素的一种功能，可以通过调节雌激素受体来挽救。使用行为， 电生理，组织化学和分子生物学技术，我们将确定的机制， 雌激素受体调节影响记忆、神经功能、胆固醇和Aβ加工的标志物， 完整和去势雄性以及完整和卵巢切除雌性中的Aβ和tau水平 家兔我们在行为、组织化学、电生理和分子生物学方面的专业知识和跟踪记录 在胆固醇喂养的兔子中进行的生物学研究使我们成为一个特别适合进行这些研究的团队。 实验，进一步验证这种非转基因模型的负载，并定位我们，以帮助了解影响 LOAD风险和治疗反应性的分子决定因素的性别差异。