CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
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DOI：
10.1038/s41586-019-1088-4
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发表时间：
2019-04-11
期刊：
影响因子：
64.8
通讯作者：
Wyss-Coray, Tony
中科院分区：
文献类型：
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作者：
Pluvinage, John V.;Haney, Michael S.;Wyss-Coray, Tony
小胶质细胞通过吞噬清除蛋白质聚集体和细胞碎片来维持中枢神经系统的稳态。这种功能在衰老和神经退行性疾病期间恶化，伴随着认知能力下降。然而，受损的小胶质细胞稳态功能的机制和恢复这种功能的认知效果仍然未知。我们将CRISPR-Cas9敲除筛选与RNA测序分析相结合，以发现小胶质细胞吞噬作用的年龄相关遗传修饰剂。这些筛选鉴定了CD 22，一种典型的B细胞受体，作为吞噬作用的负调节剂，其在老年小胶质细胞上上调。CD 22介导α 2，6-连接唾液酸的抗吞噬作用，并且抑制CD 22促进体内髓鞘碎片、淀粉样蛋白-β寡聚体和α-突触核蛋白原纤维的清除。阻断CD 22功能的抗体的长期中枢神经系统递送将小胶质细胞重新编程为稳态转录状态并改善老年小鼠的认知功能。这些发现阐明了与年龄相关的小胶质细胞损伤的机制和恢复衰老大脑内稳态的策略。
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of alpha 2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-beta oligomers and alpha-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.