Consequences of Estrogen Deficiency on Neuroinflammation and Cognitive Impairments

雌激素缺乏对神经炎症和认知障碍的影响

• 批准号: 10387671
• 负责人: Kevin Sanchez
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2025-01-11
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387671
• 关键词: Ablation; Address; Affect; Affective; Age; Aging; Anti-Inflammatory Agents; Antiinflammatory Effect; Behavior; Behavioral; Biological Markers; Brain; Brain region; Cells; Cessation of life; Circadian Dysregulation; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Dependence; Deterioration; Development; Environment; Estradiol; Estrogens; Exhibits; Foundations; Genes; Goals; Hippocampus (Brain); Hormones; Immune; Immunocompetent; Impaired cognition; Individual; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Life; Link; Literature; Mediating; Menopause; Microglia; Moods; Morphology; Mus; Neuroimmune; Neuroimmune system; Neuroimmunomodulation; Operative Surgical Procedures; Outcome; Ovarian; Ovariectomy; Pathway interactions; Performance; Phenotype; Physiological; Pilot Projects; Postmenopause; Predisposition; Property; Reporting; Research; Risk; Risk Factors; Social Behavior; Stimulus; Stress; Testing; Tissues; Woman; Wood material; Work; base; brain cell; cell type; cognitive change; cognitive performance; cytokine; differential expression; disability; experimental study; high risk; improved; in vivo; neuroinflammation; new therapeutic target; prevent; receptor; response; targeted treatment; therapy development

PROJECT SUMMARY Cognitive impairment and dementia are significant causes of disability, dependency, and death, with an estimated 50 million individuals currently dealing with dementia worldwide. Estrogen loss, such as after natural or surgically induced menopause, is linked to a heightened susceptibility to cognitive decline. Moreover, women who become estrogen-deficient earlier in life have an even higher risk of developing cognitive impairments; however, the mechanisms mediating the association between estrogen loss and cognitive dysfunction are not fully understood. Estrogens can interact with receptors ubiquitously expressed in the brain to exert anti- inflammatory properties. In addition, they may regulate the neuroimmune system by interacting with microglia, the primary innate immune cell of the brain. Microglial activation and the subsequent release of inflammatory molecules can drive a suite of physiological and behavioral alterations that can worsen cognitive outcomes. Furthermore, an emerging body of literature suggests that in response to a previous condition (e.g., aging, stress, circadian disruption), microglia can become primed. Microglial priming is a term used to describe the shift towards a baseline sensitized inflammatory phenotype characterized by an amplified response to an inflammatory stimulus. Here, we propose that estrogen loss can act as an antecedent condition that primes microglia to the neuroimmune changes associated with aging, causing exacerbated pro-inflammatory responses that may contribute to cognitive decline. There is currently a lack of understanding behind the microglia-specific mechanisms through which estrogens mitigate neuroinflammation and cognitive decline. Therefore, the overall objectives of this proposal are to (i) establish whether ovariectomy and timing of estrogen loss lead to elevated neuroinflammation that contributes to behavioral deficits, (ii) assess if microglia become primed in response to ovariectomy, and (iii) determine whether microglia are critical for generating cognitive impairments with ovariectomy and aging. The central hypothesis is that ovariectomy, particularly earlier in life, raises vulnerability to adverse cognitive changes by eliciting an exaggerated neuroimmune response through priming (i.e., sensitizing) microglia to aging. Two specific aims are proposed to test this hypothesis. The experiments outlined in Aim 1 will investigate whether ovariectomy and earlier estrogen loss prime the neuroimmune system, leading to deficits in affective and cognitive behaviors. In Aim 2, microglia will be ablated in vivo to determine whether neuroinflammation and behavioral deficits are curtailed in the absence of microglia. These findings will establish if microglia are the cell type responsible for the neuroimmune and behavioral changes induced by estrogen loss. Overall, this proposal will help advance the understanding of cognitive impairments in post-menopausal women and may lead to novel therapies for targeting the cognitive decline associated with aging.

项目概要 认知障碍和痴呆是残疾、依赖和死亡的重要原因， 据估计，目前全世界有 5000 万人患有痴呆症。雌激素损失，例如自然发生后 或手术引起的更年期，与认知能力下降的易感性增加有关。而且，女性 早年雌激素缺乏的人出现认知障碍的风险更高； 然而，介导雌激素减少和认知功能障碍之间关系的机制并不明确。 完全明白了。雌激素可以与大脑中普遍表达的受体相互作用，发挥抗- 炎症特性。此外，它们可能通过与小胶质细胞相互作用来调节神经免疫系统， 大脑的主要先天免疫细胞。小胶质细胞激活和随后的炎症释放 分子可以驱动一系列生理和行为改变，从而恶化认知能力 结果。此外，新兴的文献表明，为了应对先前的条件（例如， 衰老、压力、昼夜节律紊乱），小胶质细胞可能会被激活。小胶质细胞启动是一个术语，用于描述 向基线致敏炎症表型的转变，其特征是对某种物质的放大反应 炎症刺激。在这里，我们建议雌激素损失可以作为启动的前提条件 小胶质细胞与衰老相关的神经免疫变化，导致促炎症反应加剧 这可能会导致认知能力下降。目前对小胶质细胞特异性背后缺乏了解 雌激素减轻神经炎症和认知能力下降的机制。因此，总体 该提案的目标是 (i) 确定卵巢切除术和雌激素丧失时间是否会导致 导致行为缺陷的神经炎症，（ii）评估小胶质细胞是否会响应 卵巢切除术，以及（iii）确定小胶质细胞是否对于产生认知障碍至关重要 卵巢切除术和衰老。中心假设是卵巢切除术，尤其是在生命早期，会增加脆弱性 通过启动（即， 敏）小胶质细胞对衰老。提出了两个具体目标来检验这一假设。实验概述 目标 1 将研究卵巢切除术和早期雌激素丧失是否会启动神经免疫系统，从而导致 情感和认知行为缺陷。在目标 2 中，将在体内消融小胶质细胞以确定是否 如果没有小胶质细胞，神经炎症和行为缺陷就会减少。这些发现将确定 如果小胶质细胞是负责雌激素丧失引起的神经免疫和行为变化的细胞类型。 总体而言，该提案将有助于增进对绝经后女性认知障碍的理解 并可能导致针对与衰老相关的认知能力下降的新疗法。