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 多项临床证据表明肺炎、认知障碍和痴呆之间存在联系 然而，在老年人中，这种易感性的机制仍不清楚。 检验以下假设：老小胶质细胞中蛋白质稳态的丧失会导致持续的适应不良反应 免疫损伤阻碍了严重病毒感染后神经元可塑性和认知能力的恢复 为了实现这一目标，巴丁格/米沙林实验室开发了一种肺炎小鼠模型。 使用甲型流感病毒，我们将用它来比较年轻和年老动物和模型的认知恢复情况 我们的初步转录组学数据来自大量脑组织并经过流式排序。 小胶质细胞表明，老年动物的小胶质细胞会出现显着的蛋白质稳态功能障碍，并采用亲 稳定状态下的炎症表型会因整合的持续激活而加剧。 肺炎后的应激反应，除了抗原呈递和胶质生成的异常增加 我们发现衰老和 AD 中的小胶质细胞蛋白质稳态缺陷可能会损害体内平衡。 功能并“引发”对感染的异常反应，导致神经退行性变和认知障碍 在这个提议中，我们将首先测试小胶质细胞对于认知的启动是否是必需的。 然后我们将确定是否使用药物消融对衰老和 AD 小鼠模型造成损害。 老年肺炎和 AD 后的认知缺陷可以通过抑制 ISR 来挽救 最后，我们将确定小胶质细胞中 ISR 的激活是否单独起作用。 使用 ISR 的基因操作对于 AD 认知障碍的沉淀是必要或充分的 这项研究将有助于严格评估感染在散发性疾病发展中的作用。 痴呆症，并可能有助于开发针对与年龄相关的认知障碍的预防性疗法。