Innate Immune Responses to SARS-CoV-2 in AD mouse models

研究综述 突发性嗅觉丧失已被认为是新冠肺炎早期的常见症状 大流行的影响。新冠肺炎患者的嗅觉缺陷程度是否预示着 神经疾病还没有得到仔细的评估。嗅觉功能障碍是公认的早期 痴呆症的症状，尤其是阿尔茨海默氏症和帕金森氏症。最近的人类研究发现， SARS-CoV-2感染与阿尔茨海默病的早期发病有关。使用鼠标模型，我们 观察到稀疏SARS-CoV-2感染时嗅觉上皮炎性反应扩大。 据报道，在病毒感染下，嗅觉受体普遍下调，这表明 可能是嗅觉上皮局部病毒感染造成的分布式病毒影响。我们假设 由SARS-CoV-2引发的嗅觉上皮广泛的炎症反应增强了 家族性阿尔茨海默病突变导致的疾病进展加速的影响。在这项研究中，我们 将表征对SARS-CoV-2在嗅上皮和嗅球的炎症反应 阿尔茨海默病小鼠模型；我们将进一步确定SARS-CoV-2感染诱导的嗅觉 阿尔茨海默病小鼠模型的功能缺陷。通过这项研究，我们将了解遗传背景 SARS-CoV-2感染相关分子和组织学改变这项初步研究还将确立 以嗅觉通路为切入点研究嗅觉相关分子机制的前提 阿尔茨海默病的发病机制。

RESEARCH SUMMARY Sudden-onset of olfactory loss has been recognized as a common COVID-19 symptom during the early phase of the pandemic. Whether the degree of olfactory deficit in COVID-19 is indicative of any long-term neurological diseases has not been carefully evaluated. Olfactory dysfunction is well recognized as an early symptom of dementia, particularly in Alzheimer’s and Parkinson’s diseases. Recent human study identified that SARS-CoV-2 infection is associated with early onset of Alzheimer’s disease. Using mouse models, we observed expanded inflammatory responses in the olfactory epithelium upon sparse SARS-CoV-2 infection. Widespread olfactory receptor downregulation has been reported under viral infection suggesting that there might be a distributed viral impact from localized viral infection in the olfactory epithelium. We hypothesize that widespread the inflammatory response in the olfactory epithelium, triggered by SARS-CoV-2, enhances the impact of familial Alzheimer’s disease mutations resulting accelerated disease progression. In this study, we will characterize inflammatory responses to SARS-CoV-2 in the olfactory epithelium and the olfactory bulb in Alzheimer’s disease mouse models; and we will further determine SARS-CoV-2 infection induced olfactory functional deficits in AD mouse models. Through this study, we will gain understanding of genetic background dependent molecular and histological changes upon SARS-CoV-2 infection. This pilot study will also establish premise for using olfactory pathway as an entry point to investigate the molecular mechanisms involved in Alzheimer’s disease pathogenesis.