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: 10491705
• 负责人: Nicole Koutsodendris
• 金额: $ 3.96万
• 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/10491705
• 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.

项目总结 阿尔茨海默病(AD)是一种进行性神经退行性疾病，是导致死亡的第六大原因 在美国，每年花费3050亿美元。阿尔茨海默病最强的遗传风险因素是ε4变种 APOE基因(APOE4)，在60-75%的AD患者中发现。尽管载脂蛋白E4在AD中很重要， 载脂蛋白E4在AD发病机制中的确切作用尚不清楚。拟议的研究将填补 通过解剖apoE4的不同细胞来源如何调节tau病理， 阿尔茨海默病的神经炎症和神经退行性变。 最近发现apoE4导致tau病理增加和神经变性。而当 载脂蛋白E4对神经元存活和认知的不利影响取决于它是在神经元还是在 星形胶质细胞，尚不清楚神经元和星形胶质细胞载脂蛋白E4是否差异地调节tau病理和 神经变性，这是阿尔茨海默病的两个重要标志。此外，目前还不清楚apoE4是否可以直接诱导 如果apoE4对tau的影响主要是由apoE4对其他病理的影响所驱动的。 本申请中拟议的研究将确定apoE4是否可以直接导致tau病理，以及apoE4是否 载脂蛋白E4对tau病理和神经变性的影响依赖于其产生的细胞来源。 载脂蛋白E4也可能在神经炎性细胞的激活中发挥重要作用，因为它导致 小胶质细胞增多症和星形胶质细胞增多症。小胶质细胞的枯竭也被发现可以减少tau的病理程度和 神经退行性变。然而，尚不清楚移除神经元或星形细胞载脂蛋白E4是否会对 神经炎性细胞的激活及其对神经炎性细胞介导的神经退行性变的影响。 总之，拟议的研究将检验神经细胞和星形细胞载脂蛋白E4表达的中心假设 差异驱动tau病理，激活神经炎性细胞，以及随后的神经变性。这个 中心假说将在共表达P301S突变tau和loxP-Floated人的小鼠身上进行研究 APOE亚型，其中人APOE基因可通过表达GFAP-CRE或在星形胶质细胞中缺失 通过SYN1-Cre的表达来表达神经元。我将实现两个目标：(1)确定载脂蛋白E4的有害影响 关于tau的病理和神经退变都依赖于它的细胞来源，以及(2)阐明tau的作用 不同细胞来源载脂蛋白E4对神经炎症及神经炎性细胞介导的影响 神经退行性变。拟议的研究将阐明载脂蛋白E4相关AD的基本机制 并可能为未来的AD治疗确定新的靶点。