Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus
Open accessAbstract
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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SHIP1 deficiency has been shown to increase developmental synapse pruning in mice.
“Most recently, SHIP1 deficiency has been shown to increase developmental synapse pruning in mice75.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [75]
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References 114 · Cited by 34
- Authors
- Matera, A., Compagnion, A.-C., Pedicone, C., Kotah, J. M., Ivanov, A., Monsorno, K., Labouèbe, G., Leggio, L., Pereira-Iglesias, M., Beule, D., Mansuy-Aubert, V., Williams, T. L., Iraci, N., Sierra, A., Marro, S. G., Goate, A. M., Eggen, B. J. L., Kerr, W. G., & Paolicelli, R. C.
- Affiliations
- University of Lausanne (CH)
- Icahn School of Medicine at Mount Sinai (US)
- University Medical Center Groningen (NL)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University of Catania (IT)
- University of Cambridge (GB)
- Ikerbasque (ES)
- SUNY Upstate Medical University (US)
- Corresponding author
- Paolicelli, Rosa C.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2025-01
- Volume
- 58
- Issue
- 1
- Pages
- 197-217.e13
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W4405185892
- Cited by
- 34
- References
- 114
- Citations by year
- 2026: 18 · 2025: 16
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- IRIS (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- European Research Council (REMIND 804949)
- Ministero dell’Istruzione, dell’Università e della Ricerca (PONa3_00136)
- European Regional Development Fund (PID2022-136698OB-I00)
- JPB Foundation
- Ministerio de Ciencia e Innovación
- Foundation for the National Institutes of Health (U01AG058635, RO1 AG059717)
- Université de Lausanne
- National Institutes of Health
- Eusko Jaurlaritza (PIBA 2020_1_0030, IT1473-22)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- SHIP1, microglia, synaptic pruning, complement system, hippocampus development, brain development, synaptic remodeling, cognitive impairment, neurodegeneration, Alzheimer's disease risk, iPSC-derived microglia, lipid phosphatase
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Alzheimer Disease, Animals, Complement System Proteins, Hippocampus, Mice, Inbred C57BL, Neuronal Plasticity, Synapses, Microglia, Mice, Knockout, Mice, Induced Pluripotent Stem Cells
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