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

Alessandro Matera¹, Anne-Claire Compagnion¹, Chiara Pedicone², Janssen M Kotah³, Andranik Ivanov⁴, Katia Monsorno¹, Gwenaël Labouèbe¹, Loredana Leggio⁵, Marta Pereira-Iglesias⁶, Dieter Beule⁴, Virginie Mansuy-Aubert¹, Tim L Williams⁷, Nunzio Iraci⁵, Amanda Sierra⁸, Samuele G Marro⁹, Alison M Goate¹⁰, Bart J L Eggen³, William G Kerr¹¹, Rosa C Paolicelli¹²

Affiliations

¹ Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
² Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Biomedical Sciences, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴ Core Unit Bioinformatics, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁵ Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
⁶ Achucarro Basque Center for Neuroscience, Barrio Sarriena s/n, Leioa, Spain; Department of Neuroscience, University of the Basque Country EHU/UPV, Barrio Sarriena s/n, Leioa, Spain.
⁷ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
⁸ Achucarro Basque Center for Neuroscience, Barrio Sarriena s/n, Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country EHU/UPV, Barrio Sarriena, Leioa, Spain; Ikerbasque Foundation, Bilbao, Spain.
⁹ Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neurosciences, Black Family Stem Cell Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
¹⁰ Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA; Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA.
¹² Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. Electronic address: rosachiara.paolicelli@unil.ch.

PMID: 39657671
DOI: 10.1016/j.immuni.2024.11.003

Free article

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

Alessandro Matera et al. Immunity. 2025.

Free article

. 2025 Jan 14;58(1):197-217.e13.

doi: 10.1016/j.immuni.2024.11.003. Epub 2024 Dec 9.

Authors

Affiliations

¹ Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
² Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Department of Biomedical Sciences, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴ Core Unit Bioinformatics, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁵ Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
⁶ Achucarro Basque Center for Neuroscience, Barrio Sarriena s/n, Leioa, Spain; Department of Neuroscience, University of the Basque Country EHU/UPV, Barrio Sarriena s/n, Leioa, Spain.
⁷ Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
⁸ Achucarro Basque Center for Neuroscience, Barrio Sarriena s/n, Leioa, Spain; Department of Biochemistry and Molecular Biology, University of the Basque Country EHU/UPV, Barrio Sarriena, Leioa, Spain; Ikerbasque Foundation, Bilbao, Spain.
⁹ Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neurosciences, Black Family Stem Cell Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
¹⁰ Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA; Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA.
¹² Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. Electronic address: rosachiara.paolicelli@unil.ch.

PMID: 39657671
DOI: 10.1016/j.immuni.2024.11.003

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.

Keywords: AD risk genes; Alzheimer’s disease; INPP5D; SHIP1; cognitive dysfunction; complement; microglia; synaptic pruning.

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Conflict of interest statement

Declaration of interests A.M.G. serves on the SRB of Genentech and the SAB of Muna Therapeutics. A.M.G. received funding from JPB Foundation and NIH U01AG058635. W.G.K. and C.P. have a patent pending regarding the use of human iPSCs that have been gene edited at the SHIP1/INPP5D locus for use as a cell therapy in dementias.

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

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

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