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.

项目概要 阿尔茨海默氏病 (AD) 是一种进行性神经退行性疾病，是导致以下疾病的最常见原因 老年人群中出现严重痴呆症。目前，尚无批准的疗法可以对抗该疾病 AD 背后的机制，强调需要开发更多、有效的治疗方法。 AD很经典 其特征是β-淀粉样蛋白（Aβ）斑块、神经原纤维缠结（NFT）和全脑神经炎症。到 成功地创造出治疗 AD 的疗法，这些病理特征背后的机制必须更好 明白了。最近，全基因组关联研究（GWAS）表明许多骨髓基因与 AD 的调制。在中枢神经系统中，小胶质细胞是主要的髓系细胞，因此， 表明小胶质细胞参与 AD。然而，目前尚不清楚的是，小胶质细胞是否参与 AD 是有益的还是有害的。小胶质细胞消融研究和全球小胶质细胞基因敲除研究表明 结果相互矛盾，可能是因为这些研究要么全局改变基因转录，要么针对所有小胶质细胞 当 AD 中存在多个小胶质细胞亚群时。迄今为止，还不可能有选择地针对这些 离散的小胶质细胞群体以确定它们的相对作用和功能。为此，我们开发了 选择性靶向和调节斑块相关小胶质细胞同时保留非斑块的两种方法 相关的小胶质细胞不受影响。因此，我建议 1) 确定斑块相关小胶质细胞的贡献 通过针对该基因的新型可诱导不稳定的 cre-lox 小鼠品系来研究 AD 的发病机制 负责小胶质细胞对 Aβ 斑块、TREM2 的反应，以及 2) 证明能够 通过药理学改变斑块相关小胶质细胞的形态和转录特征 聚酰胺胺羟基树枝状聚合物的全身给药。总的来说，该提案将阐明其作用 AD 中斑块相关的小胶质细胞的研究，并展示了这些细胞的潜在治疗方法，从而导致 更清楚地了解小胶质细胞在 AD 结局中的作用。