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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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】：男性和女性在迟发性心脏病的发生率和严重程度方面存在显着差异。更年期后，女性更容易出现 LOAD 和症状。包括认知障碍在内的疾病的症状会因高浓度而加剧。胆固醇是中年时期 LOAD 的主要危险因素，但我们对其如何发生的了解还存在很大差距。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的差异——一种非常规但有前途的模型这些兔子在 AD 样病理、雌激素受体转录方面表现出显着的性别差异。胆固醇喂养的雌性兔子会产生β活性和蛋白质表达以及认知差异。淀粉样蛋白 (Aβ) 沉积速度比胆固醇喂养的男性慢，并且通过消除外周雌激素卵巢切除术使 Aβ 水平增加一倍以上，表明雌激素具有保护作用。胆固醇饮食显着改变雌激素受体，增加血清和海马的雌激素水平胆固醇代谢物、27-羟基胆固醇 (27-OHC) 和雌性胆固醇喂养兔子记得 27-OHC 依赖海马的学习能力优于胆固醇喂养的男性。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，我们有证据表明喂食胆固醇的兔子会出现 27-OHC 升高和记忆缺陷的情况。我们也有数据显示存在性行为。雌激素受体转录活性和突触前蛋白表达的差异喂食胆固醇的雌性兔子的活性区和突触后密度高于雄性兔子。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 LOAD 的一个重要危险因素，并且如上所述，27-OHC 在 MCI 和 LOAD 中升高。在三个具体目标中，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）用胆固醇喂养的兔子来检验 AD 样认知障碍和病理学中性别差异的假设是雌激素的功能，可以通过雌激素受体调节来挽救。电生理学、组织化学和分子生物学技术，我们将通过以下方式确定其机制：雌激素受体调节会影响记忆、神经功能、胆固醇标记物和 Aβ 加工，胆固醇喂养的完整和去势男性以及完整和卵巢切除女性的 Aβ 和 tau 水平我们在行为、组织化学、电生理学和分子方面的专业知识和跟踪记录。对胆固醇喂养的兔子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 LOAD 的非转基因模型，并使我们能够帮助理解其影响性别差异对 LOAD 风险和治疗反应的分子决定因素的影响。