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: 10553104
• 负责人: Kevin Sanchez
• 金额: $ 2.03万
• 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 2023-05-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553104
• 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; Estrogen decline; Estrogen deficiency; Estrogens; Exhibits; Foundations; Genes; Goals; Hippocampus; 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; 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; Work; brain cell; cell type; cognitive change; cognitive performance; cytokine; differential expression; disability; experimental study; glial activation; high risk; improved; in vivo; neuroinflammation; neuroprotection; new therapeutic target; prevent; receptor; response; surgical menopause; 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.

项目摘要 认知障碍和痴呆症是残疾，依赖和死亡的重要原因， 估计目前在全球范围内处理痴呆症的人估计有5000万人。雌激素损失，例如自然之后 或通过手术诱导的更年期，与认知能力下降的敏感性增强有关。而且，女性 在生命早期变得雌激素缺乏的人患认知障碍的风险甚至更高。 但是，介导雌激素丧失和认知功能障碍之间关联的机制不是 完全理解。雌激素可以与在大脑中泛表达的受体相互作用，以发挥抗 - 炎症特性。此外，它们可以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炎症的释放 分子可以驱动一套生理和行为改变，这会使认知能力恶化 结果。此外，新兴的文献表明，在响应先前的情况下（例如， 衰老，压力，昼夜节律破坏），小胶质细胞可能会引发。小胶质启动是一个用于描述的术语 向基线敏感的炎症表型的转变，其特征是对 炎症刺激。在这里，我们建议雌激素损失可以充当素质的前提条件 与衰老相关的神经免疫性变化的小胶质细胞，导致恶化的促炎反应 这可能导致认知能力下降。当前在小胶质细胞特异的背后缺乏了解 雌激素减轻神经炎症和认知能力下降的机制。因此，整体 该建议的目标是（i）确定卵巢切除术和雌激素损失的时机是否导致升高 导致行为缺陷的神经炎症，（ii）评估小胶质细胞是否响应于 卵巢切除术和（iii）确定小胶质细胞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，尤其是生活中的早期，会增加脆弱性 通过启动引发夸张的神经免疫反应来不利的认知变化（即 敏化）小胶质细胞对衰老。提出了两个具体目标来检验这一假设。实验概述了 在AIM 1中，将研究卵巢切除术和早期雌激素丧失素数是否为神经免疫系统，领先 在情感和认知行为中缺陷。在AIM 2中，小胶质细胞将在体内消融，以确定是否是否 在没有小胶质细胞的情况下，神经炎症和行为缺陷会减少。这些发现将建立 如果小胶质细胞是负责神经免疫性的细胞类型，而雌激素丧失引起的行为变化。 总体而言，这项建议将有助于提高对绝经后妇女认知障碍的理解 并可能导致针对与衰老相关的认知下降的新疗法。