C9orf72 deficiency promotes microglial mediated synaptic loss in aging and amyloid accumulation [bulk RNA-seq]

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes including Alzheimer's disease. Here we show that C9orf72 deficiency promotes loss of homeostatic signatures in microglia and transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72 deficient microglia also promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation, while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain of function toxicities. Mouse bulk RNA-seq: 4 samples per genotype (WT, C9KO-HET, C9KO-HOMO); 2 ages (3 months and 17 months)C9orf72基因重复扩增可引发遗传性肌萎缩侧索硬化/额颞叶痴呆（amyotrophic lateral sclerosis/frontotemporal dementia, ALS/FTD），同时导致C9orf72蛋白表达缺失，并产生具有潜在毒性的RNA与二肽重复蛋白。除ALS/FTD外，C9orf72基因重复扩增已被报道与多种神经退行性综合征相关，其中包括阿尔茨海默病（Alzheimer's disease）。本研究证实，C9orf72基因缺失会促使小胶质细胞的稳态特征丧失，并向以I型干扰素（type I IFN）特征增强为标志的炎症状态转化。此外，缺失C9orf72的小胶质细胞会触发年龄依赖性的神经元功能缺陷，尤以皮质突触修剪作用增强为著，最终导致小鼠出现学习与记忆行为异常。值得注意的是，在淀粉样蛋白积累的小鼠模型中，C9orf72缺失的小胶质细胞同样会加剧突触丢失与神经元功能缺陷，但却反常地提升了斑块清除效率。上述研究结果表明，由C9orf72表达下调所引发的小胶质细胞功能异常，会直接导致重复扩增携带者出现神经退行性病变，且该过程不依赖于功能获得性毒性机制。小鼠批量RNA测序（bulk RNA-seq）：每种基因型（WT、C9KO-HET、C9KO-HOMO）设置4个样本；涵盖2个年龄组（3月龄与17月龄）