Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.
1. Nat Neurosci. 2023 Mar;26(3):406-415. doi: 10.1038/s41593-023-01257-z. Epub 2023 Feb 6. Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease. De Schepper S(1), Ge JZ(1), Sierksma A(2)(3), Crowley G(1), Ferreira LSS(1), Garceau D(4), Toomey CE(5)(6), Sokolova D(1), Rueda-Carrasco J(1), Shin SH(7), Kim JS(7), Childs T(1), Lashley T(5)(8), Burden JJ(9), Sasner M(4), Sala Frigerio C(1), Jung S(7), Hong S(10). Author information: (1)UK Dementia Research Institute, Institute of Neurology, University College London, London, UK. (2)VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium. (3)Leuven Brain Institute, KU Leuven, Leuven, Belgium. (4)The Jackson Laboratory, Bar Harbor, ME, USA. (5)The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK. (6)Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK. (7)Department of Immunology and Regenerative Biology (IRB), Weizmann Institute of Science, Rehovot, Israel. (8)Department of Neurodegenerative diseases, UCL Queen Square Institute of Neurology, London, UK. (9)Laboratory for Molecular Cell Biology, University College London, London, UK. (10)UK Dementia Research Institute, Institute of Neurology, University College London, London, UK. soyon.hong@ucl.ac.uk. Erratum in Nat Neurosci. 2026 Mar;29(3):759. doi: 10.1038/s41593-025-02197-6. Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated synaptic engulfment in mouse models of AD. © 2023. The Author(s). DOI: 10.1038/s41593-023-01257-z PMCID: PMC9991912 PMID: 36747024 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.
