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

确定保护性 APOE3ch 变体对阿尔茨海默氏病病理的机制

基本信息

  • 批准号:
    10750905
  • 负责人:
  • 金额:
    $ 4.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-10 至 2025-08-09
  • 项目状态:
    未结题

项目摘要

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.
项目摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病,其是阿尔茨海默病最常见的病因。 老年痴呆症患者,65岁及以上。AD的特征是存在细胞外淀粉样蛋白 β斑块(Aβ)、细胞内神经元tau蛋白缠结(NFT)和全脑神经炎症。许多当前 靶向Aβ或tau发育的治疗尚未成功;因此,必须 了解这些病理特征相互作用和相互影响的机制。Aβ斑块 在疾病发作前多年发展,与临床症状(如tau扩散)无关。 此外,靶向淀粉样蛋白的免疫疗法未能显示出认知改善,尽管有显著的 Aβ负荷减少。虽然NFT样tau病理学可以在不存在Aβ的情况下发展,但A β的引入可能会导致NFT样tau病理学的发展。 Aβ原纤维显著加速NFT形成,进一步强调了更好地了解其作用的必要性。 分子间相互作用最近,一项病例研究确定了一名家族性AD PSEN 1 E280 A突变的携带者 APOE 3(APOE R136 S或APOE 3ch)中的罕见突变导致对神经变性的抵抗 沿着减少的NFT,同时仍表现出脑中淀粉样斑块负荷升高。R136 S突变 位于APOE的一个区域,已知该区域在结合脂蛋白受体和硫酸乙酰肝素中起作用 蛋白聚糖(HSPG),其已被建议促进淀粉样蛋白-β聚集和神经元摄取, 细胞外tau蛋白因此,APOE 3ch突变提供了一个独特的界面来研究 Aβ和tau。为此,我们开发了一种新的ApoEch小鼠模型, 淀粉样蛋白和tau的小鼠模型,分别为5xFAD和PS19。因此,我建议1)检查保护性 ApoEch突变在PS19小鼠中减少tau病理和挽救神经变性的作用,和2) 评估ApoEch突变在抑制Aβ相关斑块病理学方面的保护作用, 在5xFAD小鼠中的炎症。总的来说,这项建议将阐明这种独特的突变在基因组中的作用。 小鼠中Aβ和tau病理的发展和表现。

项目成果

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Kristine Minh Tran其他文献

Kristine Minh Tran的其他文献

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