In vivo modelling of human microglial alterations associated with Alzheimer's disease polygenic risk

全基因组关联研究已经确定了与阿尔茨海默病（AD）发病风险增加相关的多种遗传变异。引人注目的是，风险位点的生物统计分析最强烈地暗示先天免疫和小胶质细胞功能是AD病因学中涉及的目标途径。此外，新的统计方法允许对AD进行多基因风险评分，对最高和最低风险个体的预测准确率超过90%。为了了解多基因风险基因型对阿尔茨海默病发病和进展机制的影响，本项目将利用来自阿尔茨海默病多基因风险极端患者群体的诱导多能干细胞（IPSC）建立新的小胶质细胞模型。诱导多能干细胞将分化为小胶质细胞。将通过多种功能分析，例如对β -淀粉样蛋白和细胞应激刺激的促炎性和抗炎性反应、细胞迁移和吞噬作用，对高和低AD风险的ipsc小胶质细胞进行比较。检测方法将侧重于高含量活细胞成像，并将与工业伙伴一起开发用于药物筛选和测试的快速翻译工作。为了研究野生型和转基因AD模型小鼠体内小胶质细胞的行为及其在大脑中的稳态作用，我们将利用小胶质细胞移植建立新的人类<->小鼠嵌合模型。T

Genome wide association studies have identified multiple genetic variants that are associated with increased risk of developing Alzheimer's disease (AD). Strikingly, bio-statistical analysis of risk loci most strongly implicates innate immunity and microglia function as target pathways involved in AD etiology. Moreover, novel statistical approaches allow polygenic risk scores for AD to be assigned, with a predictive accuracy for individuals at highest and lowest risk of over 90%. To understand the impact of polygenic risk genotype on mechanisms of AD onset and progression this project will establish novel microglial models from induced pluripotent stem cells (IPSC) derived from individuals in patient cohorts identified at the extremes of polygenic risk of AD. IPSCs will be differentiated into microglia. High and low AD risk IPSCmicroglia will be compared using multiple functional assays e.g. pro- and anti-inflammatory responses to beta-amyloid and cell stress stimuli, cell migration and phagocytosis. Assays will focus on high-content live cell imaging and be developed with a view to rapid translation of work for drug screening and testing with industrial partners. To investigate microglial behavior in vivo and the homeostatic role played in brains of wildtype and transgenic AD model mice, microglial cell transplantation will be used to establish novel human <-> mouse chimeric models. T