Determining the mechanisms of the protective APOE3ch variant on Alzheimer's Disease pathologies

项目摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病，是导致 65岁及以上的老年人患有痴呆症。AD的特征是细胞外淀粉样蛋白的存在。 β斑块(Aβ)、细胞内神经原纤维tau缠结(NFT)和全脑神经炎。多流 针对Aβ或tau发展的治疗尚未成功；因此，必须 了解这些病理特征相互作用和影响的机制。Aβ斑块 发病前多年发病，与tau扩散等临床症状无关。 此外，针对淀粉样蛋白的免疫治疗未能显示出认知改善，尽管有显著的 减少β负载。虽然类似NFT的tau病理可以在没有Aβ的情况下发展，但引入 β纤维显著加速了NFT的形成，进一步突显了更好地了解其 分子相互作用。最近，一项案例研究发现了一名家族性AD PSEN1 E280A突变携带者 APOE3(APOE R136S或APOE3ch)罕见突变导致神经退行性变抵抗 同时NFT减少，同时大脑中的淀粉样斑块负荷仍然升高。R136S突变 位于已知与脂蛋白受体和硫酸乙酰肝素结合的载脂蛋白E区域 蛋白多糖(HSPGs)，已被认为是促进淀粉样蛋白-β聚集和神经元摄取 胞外tau。因此，APOE3ch突变为研究两者之间的相互作用提供了一个独特的界面 Aβ和Tau。为此，我们开发了一种新的ApoEch小鼠模型，将其与两种不同的 分别建立淀粉样蛋白和tau、5xFAD和PS19小鼠模型。因此，我建议1)审查保护性 ApoEch突变在减轻PS19小鼠tau病理和挽救神经退行性变中的作用 评估ApoEch突变在抑制β相关斑块病理和斑块中的保护作用 5xFAD小鼠的炎症反应。总的来说，这项提议将阐明这种独特的突变在 Aβ和tau两种病理在小鼠中的发展和表现。

Project Summary Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia among older adults, 65 years and older. AD is characterized by the presence of extracellular amyloid β plaques (Aβ), intracellular neurofibrillary tau tangles (NFTs), and brain-wide neuroinflammation. Many current therapeutics targeting either Aβ or tau development have not been successful; therefore, it is imperative to understand the mechanisms in which these pathological hallmarks interact and influence each other. Aβ plaques develop many years before disease onset and do not correlate with clinical symptoms like the spread of tau. Moreover, immunotherapy targeting amyloid has failed to show cognitive improvement despite the significant reduction in Aβ load. While NFT-like tau pathology can develop without the presence of Aβ, the introduction of Aβ fibrils significantly accelerates NFT formation, further highlighting the need to better understand their molecular interactions. Recently, a case study has identified a carrier of the familial AD PSEN1 E280A mutation with a rare mutation in APOE3 (APOE R136S or APOE3ch) that resulted in resistance to neurodegeneration along with reduced NFTs while still exhibiting an elevated amyloid plaque load in the brain. The R136S mutation is located in a region of APOE known to have a role in binding to lipoprotein receptors and heparan sulfate proteoglycan (HSPGs), which have been suggested to promote amyloid-β aggregation and neuronal uptake of extracellular tau. Therefore, the APOE3ch mutation provides a unique interface to study the interaction between Aβ and tau. To that end, we have developed a novel ApoEch mouse model to be crossed with two different mouse models of amyloid and tau, 5xFAD and PS19, respectively. Thus, I propose to 1) Examine the protective effect of the ApoEch mutation in reducing tau pathology and rescuing neurodegeneration in PS19 mice, and 2) Assess the protective effect of the ApoEch mutation in dampening Aβ-associated plaque pathology and inflammation in 5xFAD mice. Collectively, this proposal will elucidate the role of this unique mutation in the development and manifestation of both Aβ and tau pathologies in mice.