瑞士洛桑大学Rosa C. Paolicelli团队发现，小胶质细胞脂质磷酸酶SHIP1限制补体介导的健康发育过程中海马突触修剪。这一研究成果于2024年12月9日在线发表在国际学术期刊《免疫》上。

研究人员表示，编码脂质磷酸酶SH2含有肌醇多磷酸酯5-磷酸酶1（SHIP1）的，基因肌醇多磷酸酯-5-磷酸酶D（INPP5D）与阿尔茨海默病（AD）风险相关。它如何影响小胶质细胞功能和大脑生理尚不清楚。

研究人员展示了SHIP1在健康大脑发育早期阶段的富集。通过结合体内功能缺失方法和蛋白质组学分析，研究人员发现条件性缺失小胶质细胞SHIP1的小鼠在出生后早期表现出补体增加和突触丧失。SHIP1缺乏的小胶质细胞表现出改变的转录特征和依赖于补体系统的异常突触修剪。

只有在出生后早期小胶质细胞SHIP1被耗竭时，小鼠在成年后才会表现出认知缺陷，而在晚期阶段则没有这种缺陷。缺乏SHIP1的诱导多能干细胞（iPSC）衍生小胶质细胞也显示出增加的突触结构吞噬。这些发现表明，SHIP1对于健康发育大脑中小胶质细胞介导的突触重塑至关重要。破坏这一过程会产生持久的行为效应，并可能与神经退行性疾病的易感性相关。

附：英文原文

Title: Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus

Author: Alessandro Matera, Anne-Claire Compagnion, Chiara Pedicone, M. Kotah Janssen, Andranik Ivanov, Katia Monsorno, Gwenal Labouèbe, Loredana Leggio, Marta Pereira, Dieter Beule, Virginie Mansuy-Aubert, Tim L. Williams, Nunzio Iraci, Amanda Sierra, Samuele G. Marro, Alison M. Goate, Bart J.L. Eggen, William G. Kerr, Rosa C. Paolicelli

Issue&Volume: 2024-12-09

Abstract: The gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration.

DOI: 10.1016/j.immuni.2024.11.003

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00513-2