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

研究综述 突然发作的嗅觉丧失已被认为是早期常见的COVID-19症状 大流行病。COVID-19的嗅觉缺陷程度是否表明任何长期的 神经系统疾病尚未得到仔细评估。嗅觉功能障碍是公认的早期 痴呆症症状，特别是阿尔茨海默病和帕金森病。最近的人类研究表明， SARS-CoV-2感染与阿尔茨海默病的早期发作有关。使用小鼠模型，我们 观察到稀疏SARS-CoV-2感染后嗅上皮的炎症反应扩大。 据报道，在病毒感染下，嗅觉受体普遍下调，这表明， 可能是嗅觉上皮中局部病毒感染的分布式病毒影响。我们假设 由SARS-CoV-2引发的嗅觉上皮中广泛的炎症反应，增强了 家族性阿尔茨海默病突变的影响导致疾病进展加速。本研究 将描述SARS-CoV-2在嗅上皮和嗅球中的炎症反应， 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 AD小鼠模型中的功能缺陷。通过这项研究，我们将了解遗传背景 依赖于SARS-CoV-2感染的分子和组织学变化。这项试点研究还将建立 使用嗅觉通路作为切入点，研究参与的分子机制的前提 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.