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.

中文翻译：

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小胶质细胞脂质磷酸酶 SHIP1 限制健康发育的海马体中补体介导的突触修剪


基因肌醇多磷酸-5-磷酸酶 D （INPP5D） 编码含脂质磷酸酶 SH2 的肌醇多磷酸 5-磷酸酶 1 （SHIP1），与阿尔茨海默病 （AD） 的风险有关。它如何影响小胶质细胞功能和大脑生理学尚不清楚。在这里，我们表明 SHIP1 在健康大脑发育的早期阶段富集。通过结合 体内功能丧失方法和蛋白质组学，我们发现有条件地缺乏小胶质细胞 SHIP1 的小鼠在出生后早期大脑中表现出补体和突触丢失增加。SHIP1 缺陷型小胶质细胞表现出转录特征改变和异常突触修剪，这取决于补体系统。只有当小胶质细胞 SHIP1 在出生后早期耗尽时，小鼠在成年后才表现出认知缺陷，但在后期没有。缺乏 SHIP1 的诱导多能干细胞 （iPSC） 衍生的小胶质细胞也显示出突触结构的吞噬增加。这些发现表明，SHIP1 对于健康发育中的大脑中适当的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影响，并且可能与神经退行性变的脆弱性有关。