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

IF 25.5 1区 医学 Q1 IMMUNOLOGY
Alessandro Matera, Anne-Claire Compagnion, Chiara Pedicone, M. Kotah Janssen, Andranik Ivanov, Katia Monsorno, Gwenaël 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
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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.

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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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