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.

项目概要/摘要 阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是神经炎症 与大脑中淀粉样斑块和含有 tau 蛋白的神经原纤维缠结有关，以及严重的 迄今为止，载脂蛋白 E (APOE) 基因型与神经退行性变、神经炎症和脂质积累有关。 是晚发性 AD 最强大的遗传风险因素，被认为在 小胶质细胞和星形胶质细胞的病理激活有助于神经炎症和脂质代谢。 AD 和相关痴呆症 (ADRD) 中神经元和突触的丧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 我们的实验室最近对神经炎症和神经变性的介质知之甚少。 证明小胶质细胞免疫氧化甾醇 25-羟基胆固醇 (25HC) 增强了 促炎细胞因子 IL-1b，以 APOE 亚型依赖性方式 (E4>E3)。 羟化酶 (CH25H)，一种合成 25HC 的酶，在 AD 和 PS19 脑组织中也上调 正如在疾病相关小胶质细胞 (DAM) 中一样，我们有初步证据表明 25HC 直接导致 在 PS19 小鼠中观察到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。 我们发现激活的小胶质细胞合成和分泌的 25HC 驱动 tau 依赖性 我们将通过其调节胆固醇代谢的作用来研究神经炎症和神经变性。 假设如下——在目标 1 中，我们将确定 Ch25h 在介导 tau 依赖性中的重要性 在目标 2 中，我们将确定 Ch25h/25HC 在介导中的作用。 APOE4 对 tau 依赖性神经病理学的有害影响 在目标 3 中，我们将确定是否和 25HC 如何改变胆固醇代谢以降低神经活力 成功完成该项目可能会。 促进针对 ADRD 的新型治疗策略的开发。