COVID-19 related inflammation as a risk factor for age-related cognitive decline and Alzheimer's Disease

COVID-19 相关炎症是与年龄相关的认知能力下降和阿尔茨海默病的危险因素

• 批准号: 10646590
• 负责人: Natalie Celia Tronson
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646590
• 关键词: 2019-nCoV; APP-PS1; Acceleration; Adult; Age-associated memory impairment; Aging; Agonist; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Behavioral; Brain; COVID-19; COVID-19 impact; COVID-19 pandemic; COVID-19 survivors; Data; Dementia; Disease Progression; Female; Future; Gene Expression Profiling; Genotype; Goals; Hippocampus; Immune; Immune signaling; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Interferon Type I; Knowledge; Laboratories; Lipopolysaccharides; Long COVID; Long-Term Effects; Mediating; Memory; Memory Disorders; Memory Loss; Memory impairment; Microglia; Molecular Analysis; Mus; Nerve Degeneration; Neuroimmune; Neuroimmunomodulation; Neuronal Plasticity; Pathway interactions; Persons; Play; Population; Prevention strategy; Preventive treatment; Process; Protein Biochemistry; Protocols documentation; RNA Viruses; Recovery; Reporting; Research; Resolution; Risk; Risk Factors; Risk Reduction; Role; Senile Plaques; Sex Differences; Signal Transduction; Survivors; Symptoms; TLR3 gene; TLR4 gene; TLR7 gene; TLR8 gene; Testing; Time; Transgenic Mice; Virus; Wild Type Mouse; Woman; Work; age related; behavior test; beta amyloid pathology; chemokine; cognitive function; coronavirus disease; cytokine; dementia risk; immune activation; male; middle age; mouse model; neuroinflammation; novel; pandemic disease; post-COVID-19; sex; tau aggregation; young adult

PROJECT SUMMARY More than 85 million cases of COVID-19 have been recorded in the US alone, and up to 40% of survivors report Long-COVID symptoms including cognitive impairments. Together with evidence that inflammation during adulthood increases risk for later cognitive decline, this raises the prospect that the COVID-19 pandemic will cause a future “second pandemic” in Alzheimer’s disease and age-related dementias. In this project, we will identify specific mechanisms by which single stranded RNA (ssRNA) viruses (e.g., SARS-COV- 2) triggered innate immune signaling contributes to long-lasting memory impairments, exaggerated cognitive decline during aging, and risk for dementias including Alzheimer’s disease. Our main goal is to determine the impact of innate immune signaling as a consequence of ssRNA viruses on exaggeration of age-related cognitive decline and risk for dementias including Alzheimer’s Disease. We will use a subchronic inflammation protocol, established in my laboratory, together with behavioral tests of memory, protein biochemistry, and gene expression assays to identify persistent changes in inflammatory state and neuroplasticity mechanisms that exacerbate cognitive decline. We will use wild-type mice and APP/PS1 transgenic mice to determine whether TLR7-induced inflammation causes acceleration of age-related cognitive decline and AD-like pathology. Findings from this project will demonstrate how COVID-19, and other TLR7-induced inflammation increases risk for dementia; identify sex differences in COVID-related vulnerability to cognitive decline; and provide a basis for novel preventive strategies and treatments to reduce risk for Alzheimer’s disease and other dementias in the post-COVID-19 population.

项目总结 仅在美国就记录了8500多万例新冠肺炎病例，高达40%的幸存者 报告包括认知障碍在内的长期冠状病毒症状。再加上炎症的证据 成年后会增加日后认知能力下降的风险，这增加了新冠肺炎 大流行将导致未来阿尔茨海默病和与年龄相关的痴呆症的“第二次大流行”。在这 在这个项目中，我们将确定单链RNA(SsRNA)病毒(例如SARS-COV- 2)触发的先天免疫信号有助于持久的记忆损害，夸大认知 衰老过程中的衰退，以及包括阿尔茨海默病在内的痴呆症风险。我们的主要目标是确定 单链RNA病毒导致的先天免疫信号对年龄相关性疾病夸大的影响 认知能力下降和痴呆的风险，包括阿尔茨海默病。我们将使用一种亚慢性炎症 方案，以及记忆、蛋白质生物化学和行为测试 基因表达分析用于确定炎症状态和神经可塑性机制的持续变化 这会加剧认知能力的下降。我们将使用野生型小鼠和APP/PS1转基因小鼠来确定 TLR7诱导的炎症是否导致年龄相关性认知功能减退和AD样的加速 病理学。这个项目的发现将展示新冠肺炎和其他TLR7是如何诱导炎症的 增加患痴呆症的风险；确定与COVID相关的认知衰退易感性的性别差异；以及 为新的预防策略和治疗方法提供基础，以降低阿尔茨海默病和其他疾病的风险 后新冠肺炎时代人群中的痴呆症。