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

项目摘要 阿尔茨海默病（AD）是一种进行性神经退行性疾病，其是阿尔茨海默病最常见的病因。 老年人中的严重痴呆症。目前，还没有批准的治疗方法可以对抗 AD背后的机制，强调需要开发更多，有效的治疗方法。AD是经典的 以β-淀粉样蛋白（Aβ）斑块、神经纤维缠结（NFT）和全脑神经炎症为特征。到 成功地创建治疗AD的疗法，这些病理标志背后的机制必须更好 明白最近，全基因组关联研究（GWAS）表明许多髓样基因参与了骨髓细胞的分化。 AD的调制在中枢神经系统中，小胶质细胞是主要的常驻骨髓细胞，因此， 表明小胶质细胞参与了AD。然而，目前尚不清楚的是， 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， 相互矛盾的结果，可能是因为这些研究要么全面改变基因转录，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。到目前为止，还不可能有选择地针对这些目标， 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，我们制定了 选择性靶向和调节斑块相关小胶质细胞同时留下非斑块的两种方法 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 通过一种新的，可诱导的不稳定的cre-lox小鼠系靶向该基因， 负责小胶质细胞对Aβ斑块的反应，TREM 2，和2）显示能够 改变斑块相关小胶质细胞的形态和转录谱， 聚酰胺胺羟基树状聚合物的全身给药。总的来说，这一建议将阐明 斑块相关的小胶质细胞在AD和展示了这些细胞的潜在治疗，导致 更清楚地了解小胶质细胞在AD结局中的作用。

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.