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.

项目概要 阿尔茨海默氏病 (AD) 是一种进行性神经退行性疾病，是导致以下疾病的最常见原因 65 岁及以上老年人中的痴呆症。 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) 和全脑神经炎症。目前很多 针对 Aβ 或 tau 蛋白发育的治疗尚未成功；因此，当务之急是 了解这些病理特征相互作用和相互影响的机制。 Aβ斑块 它在疾病发作前很多年就已形成，并且与 tau 蛋白传播等临床症状无关。 此外，针对淀粉样蛋白的免疫疗法未能显示出认知改善，尽管 Aβ 负荷减少。虽然类似 NFT 的 tau 蛋白病理学可以在没有 Aβ 存在的情况下发生，但引入 Aβ 原纤维显着加速 NFT 形成，进一步强调需要更好地了解它们 分子相互作用。最近，一项案例研究发现了家族性 AD PSEN1 E280A 突变的携带者 APOE3（APOE R136S 或 APOE3ch）中存在罕见突变，导致对神经退行性变的抵抗 随着 NFT 的减少，同时大脑中淀粉样蛋白斑块的负荷仍然升高。 R136S突变 位于 APOE 的一个区域，已知该区域具有与脂蛋白受体和硫酸乙酰肝素结合的作用 蛋白聚糖（HSPG），已被认为可以促进淀粉样蛋白 - β 的聚集和神经元对 细胞外 tau 蛋白。因此，APOE3ch突变提供了一个独特的界面来研究之间的相互作用 Aβ 和 tau。为此，我们开发了一种新颖的 ApoEch 小鼠模型，可与两种不同的小鼠杂交 淀粉样蛋白和 tau 蛋白、5xFAD 和 PS19 的小鼠模型。因此，我建议 1）检查保护性 ApoEch 突变在减少 PS19 小鼠 tau 病理学和挽救神经退行性变方面的作用，以及 2) 评估 ApoEch 突变在抑制 Aβ 相关斑块病理学中的保护作用和 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 病理学的发展和表现。