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

项目摘要 阿尔茨海默病（AD）是一种进行性神经退行性疾病，是第六大死亡原因 在美国，每年花费3050亿美元。AD最强的遗传风险因素是ε4变异， APOE基因（APOE 4），在60-75%的AD患者中发现。尽管apoE 4在AD中的重要性， apoE 4在AD发病机制中的确切作用仍然知之甚少。这些研究将填补 通过剖析apoE 4的不同细胞来源如何调节tau病理学， 神经炎症和阿尔茨海默病中的神经变性。 最近发现，apoE 4导致tau病理学和神经变性增加。而 apoE 4对神经元存活和认知的有害作用取决于它是在神经元中产生还是 对于星形胶质细胞，尚不清楚神经元和星形胶质细胞apoE 4是否差异调节tau病理学， 神经变性，这是AD的两个关键标志。此外，目前还不清楚apoE 4是否可以直接诱导 tau病理学或apoE 4对tau的影响是否主要由apoE 4对其他病理学的影响驱动。 本申请中提出的研究将确定apoE 4是否可以直接诱导tau病理学，以及apoE 4是否可以直接诱导tau病理学。 apoE 4对tau病理学和神经变性的作用取决于其产生的细胞来源。 ApoE 4也可能在神经炎性细胞的活化中起重要作用，因为它导致神经炎性细胞的增加。 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降低了tau病理学的程度， 神经变性然而，目前尚不清楚去除神经元或星形胶质细胞的apoE 4是否会对神经元和星形胶质细胞的凋亡有保护作用。 神经炎性细胞的活化和神经炎性细胞介导的神经变性。 总之，本研究将验证神经元和星形胶质细胞apoE 4表达 差异驱动tau病理学、神经炎性细胞活化和随后的神经变性。的 将使用共表达P301 S突变tau和LoxP-floxed人tau的小鼠来研究中心假设。 apoE同种型，其中人APOE基因可以通过GFAP-Cre的表达在星形胶质细胞中缺失，或者通过GFAP-Cre的表达在星形胶质细胞中缺失。 神经元表达Syn 1-Cre。我将完成两个目标：（1）确定apoE 4的不利影响是否 对tau病理和神经变性的影响依赖于其细胞来源，以及（2）阐明 不同细胞来源apoE 4对神经炎症及神经炎症细胞介导的 神经变性这项研究将阐明apoE 4相关AD的基本机制 发病机制，并将有可能确定新的目标，为未来的AD治疗。

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.