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Perivascular SPP1 Drives Microglial Synaptic Engulfment After Ischemic Stroke

Chenchen Xu1,2,3, Xiaoxiao Li1, Nan Cheng1,3

  • 1Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China.

CNS Neuroscience & Therapeutics
|April 28, 2026
PubMed
Abstract

Insights

Targeting perivascular SPP1 in ischemic stroke (IS) reduces harmful microglia activity, preserves brain tissue and function, and offers a new therapeutic approach. This study highlights SPP1

Area of Science:

  • Neuroscience
  • Immunology
  • Vascular Biology

Background:

  • Microglia activation post-ischemic stroke (IS) can exacerbate neuronal damage and blood-brain barrier (BBB) disruption.
  • The specific vascular signals initiating detrimental microglia activity during IS are not fully understood.

Purpose of the Study:

  • To investigate the role of perivascular secreted phosphoprotein 1 (SPP1) in regulating microglia-mediated synaptic engulfment during IS.
  • To determine if SPP1 is a key vascular-derived signal that drives neuroinflammation and synaptic damage after IS.

Main Methods:

  • Mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) with or without SPP1 silencing (shSpp1).
  • Assessed cerebral perfusion, neuronal injury (Nissl, TUNEL), synaptic remodeling (proteomics, electron microscopy, immunofluorescence), glial-vascular unit (GVU) integrity, and behavioral outcomes.
  • Examined microglial synaptic engulfment in vivo and synaptic protein/mRNA levels in vitro.

Main Results:

  • MCAO/R led to increased microglial synaptic engulfment, synaptic damage, and reduced synaptic proteins in the ischemic penumbra.
  • Proteomic analysis revealed upregulated inflammatory and vascular pathways, with increased SPP1 from perivascular macrophages.
  • SPP1 silencing attenuated neuroinflammation, reduced infarct volume, improved perfusion, preserved GVU integrity, and improved behavioral deficits.

Conclusions:

  • Perivascular SPP1 drives excessive microglia-mediated synaptic engulfment and synaptic damage following IS.
  • Targeting SPP1 suppresses detrimental microglia activity, preserves BBB integrity and synaptic architecture.
  • SPP1 presents a potential therapeutic target for IS, focusing on the glial-vascular unit.
Keywords:
barrier integrityglial‐vascular unitischemic strokemicroglia synaptic engulfmentperivascular signaling

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