Connecting Alzheimer's Disease to Traumatic Synaptic Neurodegeneration

Alzheimer’s disease (AD) is a global public health crisis with unknown triggers and no disease modifying therapies. Effective treatments likely must be initiated in the early phases of biological disease, well before brain reserves of the neural substrates of cognition are depleted leading to overt clinical symptoms. These ‘preclinical’ periods and their triggering events, therefore, are highly significant areas of study. Traumatic brain injury (TBI), the leading cause of death and disability in younger individuals (under age 45) worldwide, is also the best-established epigenetic risk factor for AD. Once thought to be a monophasic injury, TBI is now known to initiate a chronic neuroinflammatory and neurodegenerative process that leads through unknown pathological mediators to dementing illnesses including AD, ADRDs, and chronic traumatic encephalopathy (CTE). Synapse loss is a common, early finding in AD, and the strongest pathological correlate of AD-induced dementia—even stronger than amyloid plaques or tau neurofibrillary tangles. Synaptic injury is also implicated in TBI in humans and in animal models. Synapses are challenging to study due to their extremely small size and admixture with 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 Nanostructure) to enable routine monitoring of synaptic health in animal models and in humans. Our preliminary data demonstrate that delayed cortical synapse loss occurs after diffuse, closed head, mild TBI in a mouse model, suggesting that synaptic neurodegeneration may lead to neurological disability following TBI and sensitize the brain to subsequent AD-related synapse loss, hastening the onset of dementia. We will characterize synaptic neurodegeneration resulting from mild TBI over the lifespan, and determine its ability to predict neuropsychological and behavioral outcomes. We will then assess complement activation—a component of the innate immune system that drives synapse loss in AD and is maladaptively activated after mild TBI— as a mechanism of synaptic neurodegeneration. We will determine whether targeting the complement pathway can improve synaptic health and improve behavioral outcomes using genetic and clinically-translatable pharmacological interventions. Finally, we will assess the impact of mild TBI on synaptic neurodegeneration related to amyloidosis and tauopathy, classic AD-related neuropathological and biochemical processes. We will determine whether complement inhibition can prevent TBI-induced potentiation of neurodegeneration in mouse models of these processes. These studies are expected to reveal intervenable links between early brain injury and long-term neurodegeneration relevant to the individuals at greater risk of AD and related brain disorders due to an earlier TBI. They will also further establish innovative synaptic imaging tools (SEQUIN) that will empower routine synaptic analysis in this and related fields.