Traumatic brain injury (TBI) is the leading cause of death and disability in adults under the age of 45, affecting ?20% of veterans from recent wars. Once thought to be a monophasic injury, TBI is now known to trigger an indolent neurodegenerative process that substantially increases the risk of Alzheimer?s and other forms of dementia for older veterans. All disability resulting from TBI stems from its disruption of functional neural networks. The mechanisms by which TBI interrupts these networks and sets up further neurodegenerative network breakdown are inadequately defined, though injury loci beyond those observed in white matter are increasingly recognized. Synaptic injury has been identified following TBI in humans and in animal models, resulting in pathological molecular, structural, and functional changes to synapses, or their frank loss. Synapse loss is also a common, early finding in Alzheimer?s disease (AD) where it is the strongest pathological correlate of AD-induced dementia?even stronger than amyloid plaques or tau tangles. Neuroinflammatory pathways are activated in a prolonged fashion after TBI in animal models and in humans, and play a central role in mediating synapse loss in AD. A better understanding of synaptic injury in TBI, and its neuroinflammatory mediators, therefore, could supply a missing and potentially interruptible structural-mechanistic connection between these conditions. Synapses, however, are very challenging to study due to their extremely small size and admixture within the extraordinarily complex subcellular milieu of mammalian neuropil. We developed an innovative, widely accessible super-resolution imaging and image analysis platform called SEQUIN (Synaptic Evaluation and QUantification by Imaging of Nanostructure) to enable routine monitoring of synaptic health in animal models and in humans. Our preliminary data demonstrate that synapse loss is a prominent feature of diffuse, closed head TBI in a militarily-relevant mouse model, and indicate that inhibition of the complement pathway (part of the innate immune system) prevents traumatic synapse loss and improves function after TBI. These findings suggest that neuroinflammatory synaptic injury leads to acute neurological disability following diffuse TBI and sensitizes the brain to subsequent neurodegenerative changes, hastening the onset of dementia. We propose to first (Aim 1) characterize regional synapse loss resulting from diffuse TBI and determine its neuropsychological and behavioral correlates at a scale impossible to achieve pre-SEQUIN. We will then (Aim 2) determine the role of the complement pathway in mediating traumatic synapse loss, and determine whether genetic and/or pharmacological targeting of this pathway can rescue synaptic endpoints and improve functional outcomes. Lastly, we will (Aim 3) determine whether and how TBI potentiates synapse loss later in life in response to the amyloid- and tau-related neurodegeneration that typifies AD. These studies are expected to reveal novel, druggable mechanisms of circuit injury after TBI that are connected to cognitive and emotional disability in returning active military, guard, and reserve personnel. They will furthermore establish innovative tools (SEQUIN) for the understanding of conditions with unique significance for veterans, and identify an intervenable mechanistic link between AD and its best-established epigenetic risk factor, brain trauma.
Traumatic brain injury (TBI) is both the leading cause of death and disability for active service members and the best established acquired risk factor for cognitive decline due to Alzheimer?s disease (AD) in aging veterans. Synapses, the nodes at which neurons connect to one another to form networks, are frequently injured in trauma. Synapses are also a common target of neurodegenerative conditions such as AD, where their loss is the strongest predictor of cognitive decline. Immune system activation in the brain (neuroinflammation) is powerfully induced by TBI, and is responsible for synapse loss in AD. This study seeks to structurally and functionally define synaptic injury in a militarily relevant model of diffuse TBI, determine the role of neuroinflammatory factors in traumatic synapse loss, and connect these findings with long-term neurodegeneration. These advances will identify new targets for improving outcomes for service members after TBI, and for preventing TBI from progressing to AD.
