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

小胶质细胞免疫-氧甾醇25-羟基胆固醇在阿尔茨海默病P301S tau转基因小鼠模型中介导神经炎症和神经变性中的作用

• 批准号: 10645467
• 负责人: ANIL G CASHIKAR
• 金额: $ 47.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645467
• 关键词: 25-hydroxycholesterol; Acceleration; Acute; Affect; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Apolipoprotein E; Astrocytes; Brain; Cells; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Cholesterol Synthesis Inhibition; Coculture Techniques; Data; Development; Disease associated microglia; Enzymes; Esterification; Female; Functional disorder; Gene Expression; Genes; Genotype; Hippocampus; Immune; Immune System Diseases; Inflammatory; Late Onset Alzheimer Disease; Lipids; Lipopolysaccharides; Measures; Mediating; Mediator; Microglia; Mixed Function Oxygenases; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phagocytes; Phagocytosis; Play; Production; Protein Isoforms; Reporting; Role; SRE-2 binding protein; Senile Plaques; Stains; Synapses; TLR4 gene; TREM2 gene; Tauopathies; Testing; Transgenic Mice; Transgenic Organisms; Variant; age related; apolipoprotein E-3; apolipoprotein E-4; brain tissue; cell type; cholesterol biosynthesis; cytokine; early onset; genetic risk factor; inhibitor; lateral ventricle; lipid metabolism; lipidomics; longitudinal analysis; male; mouse model; neuroinflammation; neuron loss; neuronal survival; neuropathology; neurotoxicity; novel therapeutic intervention; osmotic minipump; overexpression; piriform cortex; prevent; single nucleus RNA-sequencing; tau Proteins

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.

项目总结/摘要 阿尔茨海默病（Alzheimer disease，AD）是最常见的以神经炎症为特征的神经退行性疾病 与大脑中的淀粉样蛋白斑块和含tau蛋白的神经元缠结以及严重的 神经变性、神经炎症和脂质积聚。载脂蛋白E（APOE）基因型是迄今为止 这是晚发性AD最强大的遗传风险因素，被认为在以下方面发挥重要作用： 神经炎症和脂质代谢。小胶质细胞和星形胶质细胞的病理激活有助于 AD和相关痴呆（ADRD）中的神经元和突触的损失以及脂质功能障碍。 尽管小胶质细胞在tau介导的神经变性中具有重要的致病作用，但特定的小胶质细胞在tau介导的神经变性中具有重要的致病作用。 对神经炎症和神经变性的介质知之甚少。我们的实验室最近 表明小胶质细胞免疫氧化固醇25-羟基胆固醇（25 HC）增加了 促炎细胞因子IL-1b以APOE亚型依赖性方式（E4>E3）。胆固醇25- 羟化酶（CH 25 H），合成25 HC的酶，在AD和PS19脑组织中也上调 疾病相关小胶质细胞（DAM）。我们有初步证据表明，25 HC直接有助于 在PS19小鼠中观察到的年龄依赖性神经变性，并调节星形胶质细胞中的胆固醇代谢。 我们假设由活化的小胶质细胞合成和分泌的25 HC驱动tau依赖性 神经炎症和神经变性通过其调节胆固醇代谢的作用。我们将测试这个 假设如下-在目标1中，我们将确定Ch 25 h在介导tau依赖性中的重要性 神经炎症和神经变性。在目的2中，我们将确定Ch 25 h/25 HC在介导 APOE 4对tau依赖性神经病理学的有害影响。在目标3中，我们将确定 25 HC如何改变胆固醇代谢以降低神经元活力。该项目的成功完成可能 能够开发针对ADRD的新治疗策略。