Cellular Source-Dependent Effects of ApoE4 on Tau Pathology in Alzheimer's Disease

ApoE4 对阿尔茨海默病 Tau 病理学的细胞来源依赖性影响

• 批准号: 10314685
• 负责人: Nicole Koutsodendris
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-09 至 2023-08-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314685
• 关键词: Age of Onset; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Apolipoprotein E; Astrocytes; Biochemical; Biological Assay; Cell Survival; Cells; Cognition; Cognitive; Cognitive deficits; Event; Excision; Exhibits; Future; Genes; Glial Fibrillary Acidic Protein; Homozygote; Human; Knock-in Mouse; Knowledge; Late Onset Alzheimer Disease; LoxP-flanked allele; Mediating; Memory Loss; Microglia; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Phagocytes; Play; Production; Protein Isoforms; Research; Research Proposals; Role; Source; Tauopathies; Testing; United States; Variant; Work; apolipoprotein E-3; apolipoprotein E-4; astrogliosis; cell type; cerebral atrophy; cost; differential expression; drug development; genetic risk factor; in vivo; insight; mortality; neuroinflammation; neuron loss; neuronal survival; new therapeutic target; novel; protective effect; tau Proteins; tau mutation; therapeutic development; uptake

PROJECT SUMMARY Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of mortality in the United States and costs $305 billion annually. The strongest genetic risk factor for AD is the ε4 variant of the APOE gene (APOE4), which is found in 60-75% of all AD patients. Despite the importance of apoE4 in AD, the exact role of apoE4 in the pathogenesis of AD remains poorly understood. The proposed studies will fill critical gaps in knowledge by dissecting how different cellular sources of apoE4 modulate tau pathology, neuroinflammation, and neurodegeneration in Alzheimer's disease. It was recently discovered that apoE4 causes increased tau pathology and neurodegeneration. While the detrimental effects of apoE4 on neuronal survival and cognition depend on whether it is produced in neurons or astrocytes, it is unknow if neuronal and astrocytic apoE4 differentially modulate tau pathology and neurodegeneration, which are two critical hallmarks of AD. Additionally, it is unclear if apoE4 can directly induce tau pathology or if the effects of apoE4 on tau are primarily driven by the effects of apoE4 on other pathologies. The proposed studies in this application will determine if apoE4 can directly induce tau pathology and if the effects of apoE4 on tau pathology and neurodegeneration are dependent on the cellular origin of its production. ApoE4 may also play an important role in the activation of neuroinflammatory cells since it leads to increased microgliosis and astrogliosis. Depletion of microglia was also found to reduce the extent of tau pathology and neurodegeneration. Still, it is unknown if removal of neuronal or astrocytic apoE4 will have protective effects on activation of neuroinflammatory cells and on neuroinflammatory cell-mediated and neurodegeneration. In summary, the proposed studies will test the central hypothesis that neuronal and astrocytic apoE4 expression differentially drive tau pathology, activation of neuroinflammatory cells, and subsequent neurodegeneration. The central hypothesis will be investigated using mice that co-express P301S mutant tau and LoxP-floxed human apoE isoforms, in which the human APOE gene can be deleted in astrocytes by expression of GFAP-Cre or in neurons by expression of Syn1-Cre. I will accomplish two aims: (1) Determine if the detrimental effects of apoE4 on tau pathology and neurodegeneration are dependent on its cellular source, and (2) Elucidate the role of different cellular sources of apoE4 on neuroinflammation and neuroinflammatory cell-mediated neurodegeneration. The proposed research will elucidate the fundamental mechanisms of apoE4-related AD pathogenesis and will potentially identify novel targets for future AD therapies.

项目概要 阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，是第六大死因 在美国，每年花费 3050 亿美元。 AD 最强的遗传风险因素是 ε4 变体 APOE 基因 (APOE4)，存在于 60-75% 的 AD 患者中。尽管 apoE4 在 AD 中很重要， apoE4 在 AD 发病机制中的确切作用仍知之甚少。拟议的研究将填补 通过剖析不同细胞来源的 apoE4 如何调节 tau 病理学，揭示了知识中的关键差距， 阿尔茨海默病中的神经炎症和神经变性。 最近发现 apoE4 会导致 tau 病理和神经退行性病变增加。虽然 apoE4 对神经元存活和认知的有害影响取决于它是在神经元中产生还是在神经元中产生 星形胶质细胞，尚不清楚神经元和星形胶质细胞 apoE4 是否差异调节 tau 病理学和 神经退行性变，这是 AD 的两个重要标志。此外，尚不清楚apoE4是否可以直接诱导 tau 病理学，或者 apoE4 对 tau 蛋白的影响是否主要由 apoE4 对其他病理学的影响驱动。 本申请中提出的研究将确定 apoE4 是否可以直接诱导 tau 病理学以及是否 apoE4 对 tau 病理学和神经变性的影响取决于其产生的细胞来源。 ApoE4 也可能在神经炎症细胞的激活中发挥重要作用，因为它会导致 小胶质细胞增生和星形胶质细胞增生。还发现小胶质细胞的消耗可以减少 tau 病理学的程度，并且 神经变性。尽管如此，尚不清楚神经元或星形细胞 apoE4 的去除是否会对 神经炎症细胞的激活以及神经炎症细胞介导的神经变性。 总之，拟议的研究将检验神经元和星形细胞 apoE4 表达的中心假设 不同程度地驱动 tau 蛋白病理、神经炎症细胞的激活以及随后的神经退行性变。这 将使用共表达 P301S 突变 tau 和 LoxP-floxed 人类的小鼠来研究中心假设 apoE 亚型，其中人 APOE 基因可以通过 GFAP-Cre 的表达在星形胶质细胞中删除，或者在 Syn1-Cre 表达的神经元。我将实现两个目标：（1）确定 apoE4 是否会产生有害影响 tau 病理学和神经退行性变取决于其细胞来源，并且 (2) 阐明 不同细胞来源的apoE4对神经炎症和神经炎症细胞介导的影响 神经变性。拟议的研究将阐明 apoE4 相关 AD 的基本机制 发病机制，并有可能确定未来 AD 治疗的新靶点。