Dysfunction of microglial proteostasis drives neuroinflammation and cognitive decline following pneumonia

小胶质细胞蛋白稳态功能障碍导致肺炎后神经炎症和认知能力下降

• 批准号: 10349491
• 负责人: Rogan Aaron Grant
• 金额: $ 4.23万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349491
• 关键词: 2019-nCoV; Abeta clearance; Ablation; Adopted; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Antigen Presentation; Apoptotic; Area; Automobile Driving; Brain; COVID-19 pandemic; Chaperone Gene; Chronic; Clinical; Cognitive deficits; Cues; Data; Dementia; Development; Disease; Down-Regulation; Elderly; Endoplasmic Reticulum; Environment; Flow Cytometry; Functional disorder; Genes; Hippocampus (Brain); Histology; Homeostasis; Immune; Impaired cognition; Impairment; Individual; Infection; Inflammatory; Influenza A virus; Interruption; Laboratories; Lead; Link; Long-Term Potentiation; Measures; Microglia; Modeling; Molecular Chaperones; Mus; Myelin; Nerve Degeneration; Neuraxis; Neuronal Plasticity; Patients; Phagocytes; Phagocytosis; Pharmacology; Phenotype; Physiological; Play; Pneumonia; Population; Precipitation; Predisposition; Process; Public Health; Publications; Recovery; Research; Research Personnel; Risk; Role; Signal Transduction; Synapses; Systemic infection; Testing; Tissues; Training; United States; Viral Pneumonia; age related; arm; axon guidance; behavior measurement; biological adaptation to stress; brain tissue; career; clinically relevant; cognitive capacity; cognitive recovery; cytokine; exhaustion; experimental study; frontal lobe; genetic approach; genetic manipulation; insight; macrophage; mouse model; neuroinflammation; neurotoxicity; normal aging; novel; pneumonia model; prevent; prophylactic; proteostasis; response; restoration; small molecule inhibitor; systemic inflammatory response; transcriptome sequencing; transcriptomics

PROPOSAL SUMMARY / ABSTRACT Multiple lines of clinical evidence demonstrate a link between pneumonia, cognitive impairment, and dementia in the elderly. The mechanisms underlying this susceptibility, however, remain unclear. In this proposal, we will test the hypothesis that loss of proteostasis in old microglia results in a persistent maladaptive response to immune insult that precludes recovery of neuronal plasticity and cognitive capacity after severe viral pneumonia. Toward this aim, the Budinger/Misharin Laboratory has developed a murine model of pneumonia using influenza A virus, which we will use to compare cognitive recovery in young and old animals and models of Alzheimer's disease (AD). Our preliminary transcriptomics data from bulk brain tissue and flow-sorted microglia suggests that microglia in old animals develop significant proteostasis dysfunction, and adopt a pro- inflammatory phenotype in the steady state. This is exacerbated by persistent activation of the integrated stress response after pneumonia, in addition to aberrant increases in antigen presentation and gliogenic markers. We hypothesize that microglial proteostasis deficits in aging and in AD may impair homeostatic function and “prime” an aberrant response to infection, leading to neurodegeneration and cognitive impairment after insult. In this proposal, we will first test whether microglia are necessary for the initiation of cognitive impairment in murine models of aging and AD, using pharmacological ablation. We will then determine whether cognitive deficits after pneumonia in aging and AD can be rescued through inhibition of the ISR with the small- molecule inhibitor ISRIB. Finally, we will determine whether activation of the ISR in microglia, alone, is necessary or sufficient for the precipitation of cognitive impairment in AD using genetic manipulation of the ISR effector Atf4. This study will help to critically evaluate the role of infection in the development of sporadic dementia, and may aid in the development of prophylactic therapies for age-related cognitive impairment.

提案摘要 /摘要 多种临床证据表明肺炎，认知障碍和痴呆之间有联系 在过去。但是，这种敏感性的基础机制尚不清楚。在此提案中，我们将 检验以下假设：旧小胶质细胞中蛋白抑制的丧失会导致对 免疫侮辱，排除严重病毒后神经元可塑性和认知能力的恢复 肺炎。为了实现这一目标，Budinger/Misharin实验室已经开发了肺炎的鼠模型 使用影响力的病毒，我们将使用它来比较年轻动物和模型的认知恢复 阿尔茨海默氏病（AD）。我们的初步转录组学数据来自大脑组织和流程 小胶质细胞表明，旧动物中的小胶质细胞会出现明显的蛋白质功能障碍，并采用了促进 稳定状态下的炎症表型。通过集成的持续激活来加剧这一点 肺炎后的应力反应，除了抗原表现和神经胶质的异常增加外 标记。我们假设小胶质细胞蛋白质症在衰老和广告中定义可能会损害体内平衡 功能和对感染的异常反应，导致神经退行性和认知障碍 侮辱后。在此提案中，我们将首先测试小胶质细胞是否需要认知倡议 使用药物消融的鼠类衰老和AD模型的损害。然后，我们将确定是否 认知定义在衰老和AD的肺炎后定义，可以通过抑制ISR的抑制作用。 分子抑制剂ISRIB。最后，我们将确定仅小胶质细胞中ISR的激活是否是 使用ISR的遗传操纵，必要或足够的AD认知障碍沉淀 效应器ATF4。这项研究将有助于评估感染在零星发展中的作用 痴呆症，可能有助于开发与年龄相关的认知障碍的抗癌疗法。