Circulating exosomes amplify microglial responses and exacerbate synapse loss in aged ischemic stroke brain via a Complement Signaling




Jin, Kunlin
Zhang, Hongxia


0000-0003-1594-6707 (Zhang, Hongxia)

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Background: Aging is associated with striking increases in the incidences of stroke, which remains leading cause of disability in the US. Despite progress in understanding molecular mechanisms of neuronal cell death after stroke, effective treatment remains elusive. Recent studies showed systemic factors in the blood can profoundly reverse aging-related impairments, and our previous study show that aging systemic milieu could worse outcome after ischemic stroke. However, the underlying mechanism remain unclear. Method: The exosomes isolated from serum of young and old rats were intravenously injected into aged ischemic rats for 3 days, respectively. Infarct volume was determined by histology and motor deficits were assessed with neurobehavioral tests including running ladder and cylinder. Neuroplasticity was examined after treatment using Golgi-Cox staining. Complement activation and microglial phagocytosis in ischemic brain were measured by Western blot and immunostaining. Results: We found that injection of old serum exosomes into aged animals worsened age-related synaptic loss after stroke, along with increased infarct volume and motor deficits. By proteomic analysis, we found complement activity was increased in old serum exosomes, which could amplify proinflammatory microglial activation via C3a receptor, leading excessive phagocytosis of synapses after stroke. Inhibiting complement cascade or depletion of microglia reduced excessive phagocytosis and attenuated old exosomes-mediated ischemia outcome. Conclusion: Our data suggest that old serum exosomes may drive synapse loss via complement-microglia axis, leading to worsen functional deficits in aged ischemic rats. Targeting complement-microglia axis could potentially be translated into novel therapeutic intervention for ischemic stroke.