Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease

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…

• UO
  University of Pennsylvania
• WT
  Wellcome Trust

  Awards: 218278/Z/19/Z, MC_U12266B, 221634/Z/20/Z, 219906/Z/19/Z
• AS
  Alzheimer's Society
• KC
  King's College London
• UC
  University College London

  Award: MC_U12266B
• HO
  Home Office
• DF
  Deutsche Forschungsgemeinschaft

  Award: 259373024
• UD
  UK Dementia Research Institute
• MR
  Medical Research Council

  Award: MC_U12266B
• R
  RIKEN
• RL
  Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London