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JMG, SS1, Mice, Animals, Alzheimer Disease, Microglia, Osteopontin, Phagocytes, Macrophages, Phagocytosis, Disease Models, Animal, Amyloid beta-Peptides

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Nat Neurosci. 2023;26(3):406-15.







We thank our funders—UK Dementia Research Institute (UKDRI-1011) (which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK), Bright Focus Foundation Grant (A2021032S) (S.H.) and UCL Neurogenetic Therapies Programme (NgTP07) funded by Sigrid Rausing Trust (S.H.). We acknowledge Wellcome Trust Sir Henry Wellcome Fellowship (221634/Z/20/Z) (S.D.S.), Wellcome Trust 4-year Neuroscience PhD studentship (219906/Z/19/Z) (G.C.) and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 259373024—TRR 167 (S.J.). The QSBB is supported by the Reta Lila Weston Institute of Neurological Studies and UCL Queen Square Institute of Neurology (C.E.T. and T.L.). We acknowledge core funding to the MRC Laboratory for Molecular Cell Biology at University College London (award code MC_U12266B) (J.J.B.). The LMCB volume EM facility was set up with funding from the Wellcome Trust (218278/Z/19/Z). The Spp1TdT reporter mouse model was developed with funding from an anonymous organization. The Jackson Laboratory gratefully acknowledges the contribution of Kim Martens and the Genetic Engineering Technologies Service at The Jackson Laboratory for expert assistance with the work described in this publication (M.S. and D.G.)


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.


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