A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimer's disease

摘要 本补充申请的家长补助金是 R01 AG067193，“一种治疗老年科学的方法” 阿尔茨海默病”。补充提案是父补助金的延伸，标题为“老年科学” 研究阿尔茨海默病小鼠对 SARS-CoV-2 病理学恢复能力的方法”。的 扩展旨在研究存在认知障碍的情况下 COVID-19 的并发症，以及 老年小鼠模型中阿尔茨海默病的神经病理学损伤。这与翻译相关 因为患有与阿尔茨海默氏病 (AD) 相关的认知障碍的患者罹患阿尔茨海默病 (AD) 的风险增加 SARS-CoV-2 感染的并发症。涉及多种因素，包括导致认知障碍 不遵守暴露准则，例如人群混合、洗手和其他去污措施 程序。此外，许多需要不同程度重症监护的人可能接近 与可能携带病毒且健康状况类似的其他人接触。最后，令人衰弱的 AD 的影响可能本质上会增加对 SARS-CoV-2 感染严重并发症的易感性 已知发生在年老体弱的人身上。由于这些原因，调查缓解因素至关重要 与提高对感染病理后果的抵抗力有关，以防止发病率增加 和已经易感的老年人口的死亡率。鉴于发展严重的一个主要风险因素 致命的 SARS-CoV-2 病理学是衰老，因此它是老年科学概念的核心，该概念检查 生物衰老与年龄相关疾病之间通过多个过程的关系，并且衰老 干预需要针对多个衰老过程。我们设立家长补助金的目的是为了解决这个概念 公元。开发针对多种衰老过程并增强抗衰老能力的多药鸡尾酒 根据定义，AD 病理学也应提高 AD 患者对 SARS-CoV-2 病理学的抵抗力。的 该补充提案的假设是雷帕霉素、阿卡波糖和 苯基丁酸酯针对多种衰老过程，将增强对病理性衰老的抵抗力 SARS-CoV-2 感染对老年 AD 小鼠模型的影响。目标 1 将调查以下因素的影响 使用抗衰老药物混合物治疗感染 SARS-CoV-2 的 AD 小鼠。目标 2 将发展病理学 资料表明，用抗衰老药物混合物治疗 AD 小鼠将增强其恢复能力并改善 通过针对衰老过程并预防 SARS-CoV-2 引起的破坏性病理来保持健康 感染。这种方法对 AD 患者具有巨大的临床健康影响，但也许正如 对于处于疾病早期（例如轻度认知障碍）的个体很重要。药物的概念 可以成功提高阿尔茨海默病患者对 COVID-19 病理的恢复能力的鸡尾酒 预计将对感染风险增加的人们的健康产生重大影响。

Abstract The parent grant for this supplement application is R01 AG067193, “A geroscience approach for treating Alzheimer's disease”. The supplement proposal is an extension of the parent grant and is titled “A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimers disease”. The extension is designed to look at the complications of COVID-19 in the presence of cognitive impairment and neuropathological lesions of Alzheimer's disease in an aging mouse model. This is translationally relevant because patients with cognitive impairment related to Alzheimer's disease (AD) are at increased risk for complications of SARS-CoV-2 infection. Several factors are involved including cognitive impairment resulting in failure to follow exposure guidelines, such as crowd mingling, hand washing and other decontamination procedures. In addition, many individuals that require various levels of intensive care may come in close contact with others with similar poor health conditions that may be carrying the virus. Lastly, the debilitating effects of AD may inherently increase susceptibility to the severe complications of SARS-CoV-2 infection known to occur in older frail people. For these reasons, it is critical to investigate the mitigating factors associated with increasing resilience to pathological consequences of infection to prevent increased morbidity and mortality in an already susceptible elderly population. Given that a major risk factor for developing severe and fatal SARS-CoV-2 pathology is aging, it is thus a centerpiece for the geroscience concept that examines the relationship between biological aging and age-related diseases through multiple processes, and that aging intervention requires targeting multiple aging processes. Our parent grant is set up to address this concept for AD. The development of a multidrug cocktail that targets multiple aging processes and increases resilience to AD pathology should, by definition, also increase resilience to SARS-CoV-2 pathology in AD patients. The hypothesis of this supplement proposal is that a drug cocktail of rapamycin, acarbose, and phenylbutyrate, targeting multiple aging processes, will increase resilience to the pathological consequences of SARS-CoV-2 infection in an aging mouse model of AD. Aim 1 will investigate effects of treatment with an anti-aging drug cocktail in AD mice infected with SARS-CoV-2. Aim 2 will develop pathology profiles to show that treatment of AD mice with an anti-aging drug cocktail will enhance resilience and improve health by targeting processes of aging and prevent the devastating pathology caused by SARS-CoV-2 infection. This approach has tremendous clinical health implications for AD patients but perhaps just as important for individuals in the early stage of disease such as mild cognitive impairment. The concept of a drug cocktail that could successfully increase resilience to COVID-19 pathology in Alzheimers disease patients would be expected to have a significant impact on the health of people at increased risk for infection.