Mechanisms of Alzheimers disease pathogenesis in SARS CoV2 infection

项目总结 此申请是对我们对杜兰国家灵长类研究中心P51基本拨款的补充请求 (TNPRC)，以进一步调查SARS-CoV-2感染的急性后遗症。这 应用程序研究SARS-CoV-2导致代谢失调的主要假设 参与色氨酸代谢和DNER上调的途径，DNER是进行中的潜在标志 神经变性，导致阿尔茨海默病(AD)的进展。我们假设这些变化 新冠肺炎感染和PASC的主要致病特征，特别是神经认知 扰乱，这增加了以前感染SARS-CoV-2的人的流行率。中的更改 众所周知，Kyn/Tryp水平会加速AD。我们已发表的研究表明，系统性Kyn/Typ水平 与SARS-CoV-2感染NHP模型的肺病理严重程度相关。我们的体外研究 证明SPEK增强了海马神经元中淀粉样β蛋白的聚集和神经毒性。这个 目标1中提议的研究将利用正在进行的关于非洲绿猴(AGM)PASC的研究样本。 目的2研究将在5XFAD小鼠身上进行，这是一种公认的AD模型，以评估SARS的影响。 CoV-2Spike亚单位S1体外研究综述：Spike促进淀粉样β蛋白的加速 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 对非洲绿猴的研究为这次调查提供了所有必要的样本。此应用程序 还利用了天津核电研究院的新冠肺炎核电项目协调中心，在那里，其他三个中心和我们 从事长期CoVID研究，并将存储我们的数据以供进一步分析。此应用程序表示一个 对一个令人兴奋的假设的新探索，可能为新的和有效的治疗提供新的见解 SARS-CoV-2感染与PASC的应对策略

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.