Estrogen, Astrocyte Reactivity, and Sex Differences in Alzheimer's Disease

阿尔茨海默病中的雌激素、星形胶质细胞反应性和性别差异

基本信息

批准号：
10662993
负责人：
Serdar E. Bulun
金额：
$ 194.24万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662993
关键词：
Ablation Acceleration Age Age Months Agonist Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk American Androgens Animals Aromatase Astrocytes Autopsy Behavioral Binding Biochemical Bioinformatics Biological Brain Cell Separation ChIP-seq Chromatin Clinical Cognition Cognitive Data Data Set Dependovirus Development Epigenetic Process Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogen deficiency Estrogens Exhibits Female Gene Expression Genes Genomics Glial Fibrillary Acidic Protein Gonadal structure Hippocampus Hormones Human Immunofluorescence Immunologic Impairment Knock-out Knowledge Portal Label Link LoxP-flanked allele Magnetism Measures Mediating Medical Records Memory Memory Loss Memory impairment Microinjections Modeling Molecular Morphology Mus Nerve Degeneration Neurons Outcome Pathway interactions Perimenopause Phenotype Postmenopause Prevention strategy Production Proteins Records Reporting Research Risk Role Severities Sex Differences Signal Transduction Small Interfering RNA Synapses Testing Tissues Transgenic Organisms Western Blotting Woman age related aged analog clinically relevant conditional knockout enzyme activity genome-wide analysis human data knock-down male men mouse model neuron loss neuropathology neuroprotection neurotoxicity new therapeutic target novel novel therapeutic intervention older women pharmacologic prevent promoter sex single nucleus RNA-sequencing synaptogenesis theories transcriptome transcriptome sequencing

项目摘要

SUMMARY Nearly two-thirds of the more than 6 million Americans living with Alzheimer’s disease (AD) are women; however, the molecular mechanisms underlying this sex difference in AD vulnerability are largely unknown. Prior research has reported lower levels of estrogen in the brain of women with AD. The long-term objective of this application is to define the role of estrogen deficiency in the observed sex-specific difference in AD vulnerability. Aromatase, which converts androgens to estrogens, is mainly expressed in the brain and gonads of mice. We demonstrated that knockout of aromatase locally in the mouse brain (bArKO) or totally in whole body (tArKO) causes sex- specific memory deficits in old female mice. This phenotype is more severe in tArKO mice with estrogen deficiency throughout the body vs. bArKO mice with estrogen deficiency only in the brain. Estrogen exerts its biological action via binding to estrogen receptors (ERs). Treatment with the selective ERα agonist propylpyrazoletriol rescued memory loss in female tArKO mice. Old female tArKO, but not old male tArKO mice, exhibited fewer neurons in the hippocampus compared to wild-type littermates. RNA-seq, qPCR, and immunofluorescence analyses of the hippocampus from young or old bArKO mice of both sexes revealed astrocyte reactivity and related gene expression and morphologic changes only in old female bArKO mice. These data suggested a novel mechanism in which estrogen deficiency leads to astrocyte reactivity. We hypothesize that deficiency of estrogen/ERα signaling in the brain after menopause causes sex-specific astrocyte reactivity, resulting in AD-related neuropathology and memory loss, leading to increased AD vulnerability in females. To ascertain the mechanisms connecting estrogen deficiency in the brain to sex differences in AD vulnerability, we propose the following aims: 1. Determine whether reversal of aromatase deletion and estrogen deficiency reduces astrocyte reactivity and protects against neurodegeneration and memory loss. We will use transgenic and pharmacological approaches to restore brain aromatase expression or estrogen action in bArKO and tArKO mice at different ages. The estrogen/ERα-mediated genomic mechanisms responsible for the suppression of sex-specific hippocampal astrocyte reactivity, neurodegeneration, and memory loss will be determined using integrative genome-wide analyses employing single-nucleus (sn) RNA-seq, ERα-ChIP-seq, and snATAC-seq on freshly isolated hippocampal astrocytes. 2. Determine whether conditional knockout of ERα in hippocampal astrocytes of APPNL-G-F mice accelerates astrocyte reactivity, memory loss, and AD-related neuropathology. In parallel, we will assess estrogen levels, expression of aromatase and ERα, and sex-specific expression of reactive astrocyte-related genes in existing human datasets and postmortem hippocampal tissues and their correlation with the severity of AD pathology and memory deficits in medical records of women and age-matched men with AD. We expect that the findings from the proposed studies will identify new drug targets and lead to novel therapeutical strategies for the prevention and treatment of AD.

概括然而，在超过 600 万患有阿尔茨海默病 (AD) 的美国人中，近三分之二是女性； AD 脆弱性中这种性别差异背后的分子机制在很大程度上是未知的。据报道，患有 AD 的女性大脑中雌激素水平较低。这是该应用的长期目标。目的是定义雌激素缺乏在 AD 易感性中观察到的性别特异性差异中的作用。我们证明，它将雄激素转化为雌激素，主要在小鼠的大脑和性腺中表达。小鼠大脑中局部芳香酶（bArKO）或全身芳香酶（tArKO）的完全敲除会导致性行为- 老年雌性小鼠的特定记忆缺陷在使用雌激素的 tArKO 小鼠中更为严重。全身雌激素缺乏的小鼠与仅大脑雌激素缺乏的 bArKO 小鼠相比。通过与雌激素受体 (ER) 结合而发挥生物作用使用选择性 ERα 激动剂进行治疗。丙基吡唑三醇可以挽救老年雌性 tArKO 小鼠的记忆丧失，但不能挽救老年雄性 tArKO 小鼠的记忆丧失。与野生型同窝小鼠相比，海马体中的神经元较少。对年轻或年老 bArKO 小鼠海马体的免疫荧光分析显示仅在老年雌性 bArKO 小鼠中星形胶质细胞反应性以及相关基因表达和形态变化。数据表明雌激素缺乏导致星形胶质细胞反应性的新机制。绝经后大脑中雌激素/ERα信号传导的缺乏会导致性别特异性星形胶质细胞反应性，导致与 AD 相关的神经病理学和记忆丧失，导致女性 AD 脆弱性增加。为了确定大脑中雌激素缺乏与 AD 易感性性别差异之间的联系机制，我们提出以下目标： 1. 确定是否逆转芳香酶缺失和雌激素缺乏星形胶质细胞可降低反应性并防止神经变性和记忆丧失。恢复 bArKO 和 tArKO 中脑芳香酶表达或雌激素作用的药理学方法不同年龄的小鼠雌激素/ERα介导的基因组机制负责抑制性别特异性海马星形胶质细胞反应性、神经变性和记忆丧失将通过以下方法确定：使用单核 (sn) RNA-seq、ERα-ChIP-seq 和 snATAC-seq 进行综合全基因组分析新鲜分离的海马星形胶质细胞2.确定海马ERα是否条件性敲除。 APPNL-G-F 小鼠的星形胶质细胞加速星形胶质细胞反应、记忆丧失和 AD 相关的神经病理学。同时，我们将评估雌激素水平、芳香酶和 ERα 的表达以及性别特异性表达现有人类数据集和死后海马组织中的反应性星形胶质细胞相关基因及其女性和年龄匹配病历中 AD 病理严重程度和记忆缺陷的相关性我们预计拟议研究的结果将确定新的药物靶标并导致预防和治疗 AD 的新治疗策略。