Mild Traumatic Brain Injury and Early Onset Dementia Mouse Models and Disease Modifying Therapies

Recent reports have linked traumatic brain injury (TBI) ranging from sports athlete’s concussions to soldier blast impacts to earlier onset dementia. However, the link between mild trauma and its role in the ability to deplete a person’s “cognitive reserve” as they age leading to dementia is still unknown. Any advances in early identification tools, understanding sequela mechanism, and therapies for TBI would have significant socioeconomic and health care implications. To address this, we have developed an oxidative stress induced mouse model (Aldh2-/-), demonstrating aging-like pathology, in conjunction with a closed head weight drop injury model to mimic cognitive deficits and neuroinflammatory pathology that occurs post mild TBI. Our primary objective is to identify functional damage and future consequences induced by mTBI that contribute to increased risk of dementia. In the Aldh2-/- mice where oxidative stress (OS) represents a “1st hit”, Aldh2-/- mice exhibited increased levels of OS and accelerated cognitive deficits as early as 3 months. We further characterized this model using a chemoproteomic approach to identify a network of differentially expressed proteins linked to accelerated cognitive decline. More interestingly, when a “2nd hit” was administered such as mTBI, it led to an exacerbation of neuroinflammatory surge and post concussive syndrome 24 hrs post injury and sustained deficits in behavior up to 1 month. To utilize this model, we tested a novel library of small molecules that reactivate CREB through NO/cGMP signaling that have been previously evaluated for its anti-inflammatory, anti-convulsant, and pro-cognitive properties. Our results demonstrated a reversal of post-concussive syndrome, decrease in inflammation, and additional alleviated damage from other contributors of mTBI. This novel model of mTBI on a background strain of aging (Aldh2-/-) allows us to develop a preclinical model where disease modifying strategies for TBI can be tested.