Targeting Complement Activation Prevents Synaptic Loss and Halts Cognitive Decline in Chronic Traumatic Brain Injury. (16th November 2020)

• Record Type: Journal Article
• Authors: Alawieh, Ali M; Chalhoub, Reda; Langley, E. Farris; Mallah, Khalil; Tomlinson, Stephen
• Is Part Of: Neurosurgery. Volume 67(2010)Supplement 1
• Publication Date: 2020-11-16
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1093/neuros/nyaa447_485
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract: INTRODUCTION: Traumatic brain injury (TBI) is a risk factor for early-onset dementia. The pathological link between the acute insult and the chronic degenerative response remains unknown. Beyond the acute phase, there are currently no interventions to slow or prevent cognitive decline in TBI patients. We hypothesized that the complement system, a recognition and effector component of innate immunity, drives inflammation and synaptic loss in chronic TBI and represents an ongoing therapeutic target. METHODS: TBI was induced in adult mice (C57bl/6, 12 weeks old) using the controlled cortical impact model. Following Starting 2 months after spontaneous recovery, mice were treated with the complement inhibitor, CR2Crry, on days 56, 58 and 60. The CR2Crry construct specifically targets to sites of complement activation and inhibits complement at C3 activation. Animals were evaluated at 3 months for extent of injury using MRI, cognitive and motor outcomes using a battery of behavioral tasks, and inflammatory markers using super-resolution immunomicroscopy. RESULTS: Complement activation continued to occur and drive the expansion of an astroglial scar at 2 months after injury. The complement activation product C3d deposited on perilesional and contralateral synapses resulting in phagocytosis of synapses by microglia at 3 months post-TBI. Synaptic loss predicted worsening cognitive performance on spatial learning and memory and fear conditioning 3 months post-TBI. CR2Crry, given intravenously 2 months post-TBI, was shown to specifically target sites of complement deposition in the ipsilateral and contralateral hemisphere, and to suppress expansion of the astrogliotic scar and protect synapses from microglial-phagocytosis. Treatment with CR2Crry also significantly improved performance on all cognitive domains at 3 months post-TBI compared to vehicle treatment and compared to motor and cognitive rehabilitation therapy. CONCLUSION: The inflammatory response induced acutely after TBI progresses chronically in a complement-dependent manner and results in complement tagging of synapses for phagocytosis by microglia, leading to continuing cognitive decline. CR2Crry treatment interrupted this chronic response and reversed cognitive decline in chronic TBI, and presents the first translational anti-inflammatory treatment in development to demonstrate efficacy when administered in chronic TBI.