Selective targeting and treatment of plaque associated microglia in a mouse model of Alzheimer’s Disease

阿尔茨海默病小鼠模型中斑块相关小胶质细胞的选择性靶向和治疗

• 批准号: 10620642
• 负责人: Caden Michael Henningfield
• 金额: $ 4.43万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620642
• 关键词: Ablation; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Anti-Inflammatory Agents; Antibiotics; Blood - brain barrier anatomy; Brain; Bypass; CSF1R gene; Cells; Central Nervous System; Collaborations; Cysteine; Data; Data Set; Dementia; Dendrimers; Development; Disease; Disease Outcome; Disease Progression; Disease associated microglia; Dose; Drug Delivery Systems; Elderly; Exposure to; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Homeostasis; Hydroxyl Radical; Immune; Immunohistochemistry; Impaired cognition; Inflammatory Response; Knock-in; Knock-out; Knockout Mice; LoxP-flanked allele; Measures; Microglia; Modeling; Morphology; Mus; Myelogenous; Myeloid Cells; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Non-Prescription Drugs; Pathogenesis; Pathologic; Pathway interactions; Peripheral; Play; Population; Property; Protein Analysis; RNA; Reaction; Research; Role; Senile Plaques; Synapses; System; TREM2 gene; Tamoxifen; Target Populations; Therapeutic; Trimethoprim; brain cell; cell type; combat; cyanine dye 5; effective therapy; experimental study; extracellular; follow-up; genome wide association study; inhibitor; insight; knockout gene; mouse Cre recombinase; mouse model; neuroinflammation; novel; overexpression; pharmacologic; prevent; response; risk variant; therapeutic target; therapeutically effective; tool

Project Summary Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder which is the most common cause of severe dementia in elderly populations. Currently, there are no approved therapies which combat the mechanisms behind AD, highlighting the need to develop more, effective treatments. AD is classically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and brain-wide neuroinflammation. To successfully create therapies treating AD, the mechanisms behind these pathological hallmarks must be better understood. Recently, genome wide association studies (GWAS) have implicated many myeloid genes in the modulation of AD. In the central nervous system, microglia are the primary resident myeloid cells, thus, suggesting microglia are involved in AD. What is currently unknown, however, is whether microglial involvement in AD is helpful or harmful. Microglial ablation studies and global microglial gene knockout studies show conflicting results, possibly because these studies either globally alter gene transcription, or target all microglia when multiple subsets of microglia exist in AD. To date, it has not been possible to selectively target these discrete microglial populations to determine their relative roles and functions. To that end, we have developed two approaches to selectively target and modulate plaque associated microglia while leaving non-plaque associated microglia unaffected. Thus, I propose to 1) Determine the contribution of plaque associated microglia to the pathogenesis of AD through a novel, inducible destabilized cre-lox mouse line targeting the gene responsible for the microglial response to Aβ plaques, TREM2, and 2) Show proof of principle in being able to pharmacologically alter the morphological and transcriptional profile of plaque associated microglia through systemic administration of polyamidoamine hydroxyl dendrimers. Collectively, this proposal will elucidate the role of plaque associated microglia in AD and showcase a potential therapeutic treatment for these cells, leading to a clearer understanding of the role of microglia in AD outcomes.

项目摘要 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，是最常见的原因 古老的人群中严重的痴呆症。目前，没有批准的疗法可以打击 AD背后的机制，强调需要开发更多有效的治疗方法。广告是经典的 以β-淀粉样蛋白（Aβ）斑块，神经纤维缠结（NFTS）和范围的神经炎症为特征。到 成功创建治疗广告的疗法，这些病理标志背后的机制必须更好 理解。最近，基因组广泛的关联研究（GWAS）已在 AD的调节。在中枢神经系统中，小胶质细胞是主要居民骨髓细胞，因此 建议小胶质细胞参与AD。但是，目前未知的是小胶质的参与 在广告中是有用或有害的。小胶质消融研究和全球小胶质细胞基因敲除研究 矛盾的结果，可能是因为这些研究在全球范围内改变基因转录，或针对所有小胶质细胞 当AD中存在多个小胶质细胞时。迄今为止，不可能选择性地针对这些 离散的小胶质群体以确定其相对作用和功能。为此，我们发展了 两种选择性靶向和调节斑块相关的小胶质细胞的方法，同时留下非斑点 相关的小胶质细胞不受影响。那就是我建议1）确定斑块相关的小胶质细胞的贡献 通过针对基因的新型，诱导的不稳定的Cre-lox小鼠系的AD发病机理 负责对Aβ斑块的小胶质响应，trem2和2）显示了能够的原理证明 药理学通过牙菌体相关小胶质细胞的形态和转录特征通过 全身给药聚氨基氨基羟基树突聚合物。总的来说，该提案将阐明角色 AD中的斑块相关小胶质细胞，并展示了这些细胞的潜在治疗治疗，导致 对小胶质细胞在AD结果中的作用有更清晰的了解。