Visual system and cognitive biology in normal animals versus in an animal model of Alzheimer's disease with or without diabetes treated with solo or dual inflammasome inhibitors

摘要 阿尔茨海默病（AD）是一种进行性神经退行性疾病，占痴呆的大多数 国际吧除了认知缺陷，视觉功能障碍在AD中也很常见，可能是由于病理学原因 在视网膜上。糖尿病（DM）是导致糖尿病视网膜病变的代谢综合征， 其特征在于高血糖症、高胰岛素血症和胰岛素抵抗。DM已被确定为一个重要的 流行病学研究和临床试验中AD的危险因素和共病因素。我们最近发现了一本小说 双重NLRP 3-NLRC 4炎性小体可能导致神经病理学。在这项研究中，我们将实现 评估AD并发DM对认知、视觉和 分子病理学特征此外，使用临床前小分子抑制剂，我们将确定 NLRP 3-NLRC 4炎性小体双重抑制对AD模型中视觉和认知读数的功效 有无真正的DM。我们建议通过测试单独和双重炎性小体来解决这个问题 DM/AD联合模型中的抑制剂。我们假设双重炎性小体抑制比单独抑制好上级。 炎性小体抑制在预防DM/AD小鼠中的视觉功能障碍和认知损害中的作用。一起 这些研究将阐明合并DM/AD是否会加重视网膜和脑病变，并确定一个 潜在的治疗策略，以解决这些复杂和普遍的条件。

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegeneration that accounts for the majority of dementia worldwide. In addition to cognitive deficits, visual dysfunction is also common in AD and may be due to pathology in the retina. Diabetes mellitus (DM), the metabolic syndrome responsible for diabetic retinopathy, is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance. DM has been identified as a significant risk factor and comorbidity for AD in epidemiological studies and clinical trials. We recently identified a novel dual NLRP3-NLRC4 inflammasome that may contribute to neurologic pathology. In this study, we will achieve complementary goals of evaluating the consequences of AD complicated by DM on cognition, vision, and molecular pathological hallmarks. In addition, using preclinical small molecule inhibitors, we will determine the efficacy of dual NLRP3-NLRC4 inflammasome inhibition on visual and cognitive readouts in AD models in the presence or absence of bona fide DM. We propose to address this gap by testing solo and dual inflammasome inhibitors in models of combined DM/AD. We hypothesize that dual inflammasome inhibition is superior to solo inflammasome inhibition in preventing visual dysfunction and cognitive impairment in DM/AD mice. Together these studies will elucidate whether combined DM/AD exacerbates retinal and brain pathologies, and identify a potential therapeutic strategy to address these complex and prevalent conditions.