Perivascular cells induce microglial phagocytic states andsynaptic engulfment via SPP1 in mouse models of Alzheimer’sdisease

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/oste...

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Bibliographic Details
Published in:Nature neuroscience 2023-03, Vol.26 (3), p.406-415
Main Authors: De Schepper, Sebastiaan, Ge, Judy Z, Crowley, Gerard, Ferreira, Laís S. S, Garceau, Dylan, Toomey, Christina E, Sokolova, Dimitra, Rueda-Carrasco, Javier, Shin, Sun-Hye, Kim, Jung-Seok, Childs, Thomas, Lashley, Tammaryn, Burden, Jemima J, Sasner, Michael, Sala Frigerio, Carlo, Jung, Steffen, Hong, Soyon
Format: Article
Language:eng ; jpn
Subjects:
Alzheimer's disease
Animal models
Complement activation
Fibroblasts
Gene sequencing
Macrophages
Microglia
Neurodegenerative diseases
Osteopontin
Phagocytes
Phagocytosis
Synapses
β-Amyloid
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Summary: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.Microglia mediate aberrant synapse engulfment in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Here the authors show a perivascular cells-to-microglia crosstalk that induces microglia phagocytic state resulting in synapse engulfment in two mouse models of AD.
ISSN:1097-6256
1546-1726
DOI:10.1038/s41593-023-01257-z