Complement-Dependent Synaptic Uptake and Cognitive Decline after Stroke and Reperfusion Therapy

Abstract

Despite the success of reperfusion therapy in significantly reducing the extent of infarct expansion after stroke, the effect of revascularization on poststroke neuroinflammation and the role of anti-inflammatory strategies in postreperfusion era are yet to be explored. Here, we investigate whether the neuroinflammatory response may still contribute to neurologic deficits after reperfused stroke by using targeted complement inhibition to suppress poststroke neuroinflammation in mice with or without concurrent reperfusion therapy. Complement inhibition was achieved using B4Crry, an injury site-targeted inhibitor of C3 activation. Following embolic stroke in male C57bl/6 mice, thrombolysis using tissue-plasminogen activator (t-PA) reduced injury and improved motor deficits, but did not improve cognitive outcomes. After both reperfused and non-reperfused stroke, complement activation and opsonization of hippocampal synapses directed ongoing microglia-dependent phagocytosis of synapses for at least 30 d after stroke, leading to a loss of synaptic density that was associated with cognitive decline. B4Crry treatment, alone or in combination with tPA, limited perilesional complement deposition, reduced microgliosis and synaptic uptake, and improved cognitive outcome without affecting regenerative responses. Furthermore, complement inhibition improved the safety, efficacy, and treatment window of reperfusion therapy with t-PA by limiting hemorrhagic transformation. This work thus demonstrates that poststroke neuroinflammation contributes to hemorrhagic transformation and progression of neurodegenerative responses in the brain even following early and successful revascularization.

Proteomic Characterization of the Dynamics of Ischemic Stroke in Mice

“… 17 , 19 , 20 More recently, pharmacological inhibition of the complement cascade, including when administered within 24 h after stroke, has been shown to reduce infarct size and promote behavioral recovery. 18 , 21 − 23 These studies suggest that targeting complement proteins could be a potential neuroprotective strategy after stroke.…”

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

“…CNS synthesis of complement components is induced and maintained for extended periods of time in animal models of stroke ( Huang et al, 1999 ; Pavlovski et al, 2012 ) and traumatic brain injury ( Bellander et al, 2001 ). In extensive analyses of the different sequelae in an occlusion model of stroke—acute, subacute, and long-term—Tomlinson and colleagues have demonstrated that a fusion molecule consisting of a single-chain monoclonal antibody directed toward a stroke-induced modified annexin IV linked to the murine CR1 ortholog Cr1-related protein Y prevented opsonic C3b/iC3b deposition on neurons and prevented synaptic uptake ( Alawieh et al, 2020 ) and neuronal phagocytosis by microglia ( Alawieh et al, 2018a ). In addition, the inhibition of complement prevented microglial activation, perhaps because of reduced generation of C5a, which otherwise persisted chronically in this model.…”

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

“…The procedure can only be used in ischemic stroke patients with a proximal large artery occlusion, and many hospitals and stroke centers do not have the capability to perform the procedure. In addition, reperfusion therapy does not appear to prevent a subsequent neuroinflammatory response after stroke, and while successful reperfusion can improve motor function outcome, it does not appear to prevent cognitive decline ( 35 ). Thus, there remains an interest in developing neuroprotective strategies to treat stroke, even though very few neuroprotective agents have been shown to be unequivocally beneficial in randomized controlled clinical trials ( 36 , 37 ).…”