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Updated: Aug 11, 2025
A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of
Sebastiaan De Schepper1, Judy Z Ge1, Gerard Crowley2,3
1UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
Abstract:
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.
Insights
Secreted phosphoprotein 1 (SPP1) drives microglia to engulf synapses in Alzheimer's disease (AD) models. Blocking SPP1 prevents synaptic loss, highlighting a new therapeutic target for AD.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) involves synaptic loss, potentially driven by microglial dysfunction.
- The specific signals prompting microglia to engulf synapses in AD remain largely unknown.
Purpose of the Study:
- To investigate the role of secreted phosphoprotein 1 (SPP1) in microglia-mediated synaptic engulfment in Alzheimer's disease models.
- To elucidate the signaling pathways involved in perivascular cell-to-microglia communication in AD.
Main Methods:
- Upregulation analysis of SPP1 in perivascular macrophages and fibroblasts.
- Functional assays in AD mouse models to assess the impact of SPP1 on synaptic engulfment and loss.
- Single-cell RNA sequencing and cell-cell interaction analyses to identify molecular mechanisms.
Main Results:
- Secreted phosphoprotein 1 (SPP1) is upregulated by perivascular cells in AD mouse models.
- Perivascular SPP1 is essential for microglia to engulf synapses and upregulate phagocytic markers in the presence of amyloid-beta oligomers.
- Absence of SPP1 expression prevents synaptic loss in AD mouse models.
- SPP1 signaling induces microglial phagocytic states in the hippocampus.
Conclusions:
- SPP1 plays a critical role in perivascular cell-to-microglia crosstalk, modulating synaptic engulfment in AD.
- Targeting SPP1 may offer a novel therapeutic strategy to prevent synaptic loss in Alzheimer's disease.
