Role of the microglial immune-oxysterol 25-hydroxycholesterol in mediating neuroinflammation and neurodegeneration in the P301S tau transgenic mouse model of Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是以神经炎症为特征的最常见的神经退行性疾病 与大脑中的淀粉样斑块和含有tau的神经原纤维缠结有关，以及严重的 神经变性、神经炎症和脂质堆积。到目前为止，载脂蛋白E(APOE)基因型是 是晚发性阿尔茨海默病最强大的遗传风险因素，被认为在 神经炎症和脂类代谢。小胶质细胞和星形胶质细胞的病理性激活 在很大程度上与AD和相关痴呆(ADRD)神经元和突触的丧失以及脂质功能障碍有关。 尽管小胶质细胞在tau介导的神经变性中起着重要的致病作用，但特异性的小胶质细胞 人们对神经炎症和神经退行性变的介质知之甚少。我们的实验室最近 研究表明，小胶质细胞免疫-25-羟基胆固醇(25HC)增加了 促炎症细胞因子IL-1b以APOE异构体依赖的方式(E4和GT；E3)。胆固醇25- 合成25HC的羟基酶(CH25H)在AD和PS19脑组织中表达上调 如疾病相关的小胶质细胞(DAM)。我们有初步证据表明，25HC直接参与了 在PS19小鼠中观察到年龄依赖性神经退行性变，并调节星形胶质细胞中的胆固醇代谢。 我们假设由激活的小胶质细胞合成和分泌的25HC驱动tau依赖 通过调节胆固醇代谢而引起的神经炎症和神经退行性变。我们将对此进行测试 假设如下：在目标1中，我们将确定CH25H在调节tau依赖中的重要性 神经炎症和神经变性。在目标2中，我们将确定CH25H/25HC在调节 载脂蛋白4对tau依赖神经病理的有害影响。在目标3中，我们将确定是否和 25HC如何改变胆固醇代谢以降低神经元的活性。该项目的成功完成可能会 使针对ADRD的新的治疗策略得以开发。

PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) is the most common neurodegenerative disorder characterized by neuroinflammation associated with amyloid plaques and tau-containing neurofibrillary tangles in the brain as well as severe neurodegeneration, neuroinflammation and lipid accumulation. The apolipoprotein E (APOE) genotype is by far the most powerful genetic risk factor for late-onset AD and is thought to play an important role in neuroinflammation and lipid metabolism. Pathological activation of microglia and astrocytes contribute substantially to the loss of neurons and synapses and lipid dysfunction in AD and related dementias (ADRD). Despite an important pathogenic role for microglia in tau-mediated neurodegeneration, the specific microglial mediators of neuroinflammation and neurodegeneration are poorly understood. Our lab has recently demonstrated that the microglial immune-oxysterol 25-hydroxycholesterol (25HC) augments the production of the proinflammatory cytokine, IL-1b, in an APOE-isoform dependent manner (E4>E3). Cholesterol 25- hydroxylase (CH25H), the enzyme that synthesizes 25HC is upregulated in AD and PS19 brain tissue as well as in disease-associated microglia (DAM). We have preliminary evidence that 25HC directly contributes to the age-dependent neurodegeneration observed in PS19 mice and regulates cholesterol metabolism in astrocytes. We hypothesize that 25HC synthesized and secreted by activated microglia drives tau-dependent neuroinflammation and neurodegeneration via its effects in regulating cholesterol metabolism. We will test this hypothesis as follows – In Aim 1, we will determine the importance of Ch25h in mediating tau-dependent neuroinflammation and neurodegeneration. In Aim 2, we will determine the role of Ch25h/25HC in mediating the deleterious effects of APOE4 on tau-dependent neuropathology. In Aim 3, we will determine whether and how 25HC alters cholesterol metabolism to reduce neuronal viability. Successful completion of this project may enable the development of novel therapeutic strategies towards ADRD.