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

• 批准号: 10750905
• 负责人: Kristine Minh Tran
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10750905
• 关键词: Acceleration; Affect; Affinity; Age Months; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Anxiety; Behavior assessment; Binding; Brain; Case Study; Cells; Chronic; Clinical; Cognitive; Cognitive deficits; Dementia; Development; Disease; Disease Outcome; Elderly; Exhibits; Fluorescent in Situ Hybridization; Heparan Sulfate Proteoglycan; Human; Immune response; Immunohistochemistry; Immunotherapy; Impaired cognition; Impairment; Inflammation; Investigation; Knock-out; Link; Lipoprotein Receptor; MAPT gene; Microglia; Motor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Pathologic; Pathology; Phenotype; Protein Analysis; Reporting; Resistance; Role; Senile Plaques; Symptoms; Tauopathies; Time; Variant; abeta accumulation; apolipoprotein E-3; behavior test; behavioral outcome; cerebral atrophy; clinical phenotype; extracellular; familial Alzheimer disease; genetic risk factor; hyperphosphorylated tau; improved; insight; motor behavior; motor deficit; mouse model; mutant; neurofibrillary tangle formation; neuroinflammation; neuron loss; neuroprotection; neurotoxic; novel; presenilin-1; prevent; protective effect; protein function; receptor binding; response; tau Proteins; tau aggregation; tau-1; therapeutic development; therapeutic target; transcriptome sequencing; transcriptomics; uptake

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 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，是最常见的原因 老年人中的痴呆症，65岁及以上。 AD的特征是存在细胞外淀粉样蛋白 β斑块（Aβ），细胞内神经原纤维tau缠结（NFTS）和大脑范围的神经炎症。许多当前 针对Aβ或TAU发育的治疗尚未成功；因此，必须 了解这些病理标志相互作用和相互影响的机制。 Aβ斑块 在疾病发作之前多年发展，与临床症状无关，例如tau的扩散。 此外，靶向淀粉样蛋白的免疫疗法未能显示出认知改善目的地 减少Aβ负载。尽管不存在Aβ的NFT样tau病理可以发展 Aβ原纤维显着加速了NFT的形成，进一步强调了更好地了解其的需求 分子相互作用。最近，一个案例研究确定了家族AD PSEN1 E280A突变的载体 在APOE3（APOE R136S或APOE3CH）中具有罕见的突变，导致对神经变性的抗性 随着NFT的减少，同时仍表现出大脑中淀粉样蛋白斑块的升高。 R136S突变 位于已知在与脂蛋白受体和硫酸乙酰肝素结合中起作用的APOE区域 蛋白聚糖（HSPG），已建议促进淀粉样蛋白-β聚集和神经元摄取 细胞外tau。因此，APOE3CH突变提供了一个独特的接口来研究 aβ和tau。为此，我们开发了一种新型的Apoech鼠标模型，可以与两个不同 淀粉样蛋白和tau的小鼠模型，分别为5xFAD和PS19。那就是我建议1）检查受保护的 Apoech突变在减少tau病理学和拯救PS19小鼠中的神经退行性的影响，2） 评估Apoech突变在破坏Aβ相关斑块病理学和 5xFAD小鼠的炎症。总的来说，该提案将阐明这种独特突变在 小鼠Aβ和TAU病理的发育和表现。