Mechanisms of Alzheimers disease pathogenesis in SARS CoV2 infection

项目摘要 本申请是对杜兰国家灵长类动物研究中心P51基本资助的补充申请 （TNPRC），以进一步研究SARS-CoV-2感染后急性后遗症（PASC）。这 应用程序调查了SARS-CoV-2诱导代谢失调的总体假设， 参与色氨酸代谢的途径和DNER的上调，DNER是进行性 神经退行性变，有助于阿尔茨海默病（AD）的进展。我们假设这些改变 有助于COVID-19感染和PASC的主要致病特征，特别是神经认知 干扰，这增加了先前感染SARS-CoV-2的人的患病率。的改变 已知Kyn/Tryp水平加速AD。我们已发表的研究表明，全身Kyn/Typ水平 与SARS-CoV-2感染的NHP模型中肺部病理学的严重程度相关。我们的体外研究 证明了刺突增强海马神经元中的淀粉样蛋白β聚集和神经毒性。的 目标1中提出的研究将利用正在进行的非洲绿色猴（AGM）PASC研究的样本。 目的2研究将在5XFAD小鼠中进行，5XFAD小鼠是一种成熟的AD模型，以评估SARS的影响。 CoV-2刺突亚基S1概括了刺突增强淀粉样蛋白β加速的体外研究 聚集和斑块形成导致认知障碍。此应用程序利用我们正在进行的PASC 在非洲绿色猴中进行的研究提供了本研究所需的所有样本。本申请 还利用了TNPRC的COVID-19 NHP协调中心，其他三个中心和我们 正在从事长期新冠肺炎研究，并将存款我们的数据作进一步分析。此应用程序代表一个 对一个令人兴奋的假设进行新的调查，可能为新的和有效的治疗方法提供新的见解。 SARS-CoV-2感染和PASC的策略。

PROJECT SUMMARY This application is a supplement request to our P51 base grant to Tulane National Primate Research Center (TNPRC) to further the investigation of the Post-Acute Sequelae of SARS-CoV-2 infection (PASC). This application investigates the overarching hypothesis that SARS-CoV-2-induced dysregulation of metabolic pathways involved in tryptophan metabolism and upregulation of DNER, a potential marker of ongoing neurodegeneration, contributes to Alzheimer’s disease (AD) progression. We hypothesize that these alterations contribute to major pathogenic features of CoVID-19 infection and PASC, particularly neurocognitive disturbances, which have increased prevalence in persons previously infected with SARS-CoV-2. Alterations in the Kyn/Tryp levels are known to accelerate AD. Our published studies have shown that systemic Kyn/Typ levels correlate with the severity of lung pathology in the NHP model of SARS-CoV-2 infection. Our in-vitro studies demonstrate that spike enhances amyloid beta aggregation and neurotoxicity in hippocampal neurons. The studies proposed in Aim 1 will utilize samples from ongoing studies on PASC in African Green monkeys (AGMs). Aim 2 studies will be performed in 5XFAD mice, a well-established AD model, to assess the impact of SARS- CoV-2 Spike subunit S1 to recapitulate in vitro studies that Spike enhances the acceleration of amyloid beta aggregation and plaque formation leading to cognitive impairment. This application leverages our ongoing PASC studies in the African green monkey providing all the necessary samples for this investigation. This application also takes advantage of the CoVID-19 NHP Coordinating Center at TNPRC, where three other Centers and we are engaged in Long-CoVID studies and will deposit our data for further analysis. This application represents a novel inquiry into an exciting hypothesis that may provide new insights into novel and effective therapeutic strategies for SARS-CoV-2 infection and PASC.