Abstract #3: APP Secretases As Therapeutic Targets for Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a significant risk factor for the development of Alzheimer's disease, and post mortem studies show that 30% of TBI fatalities have amyloid- 2 (A 2 ) deposits. Remarkably, these deposits occur less than one day after injury. Not only does A 2 accumulate after TBI, but so do the necessary amyloid precursor protein (APP) enzymes responsible for A 2 production: BACE1 protein ( 2 -secretase) and the gamma-secretase complex protein presenilin-1 (PS-1). In order to understand the role of these secretases in brain trauma, we targeted 2 - and gamma-secretases with genetic knockout (BACE1−/−) and pharmacological inhibition (DAPT treatment) in an experimental model of TBI. We exposed WT and BACE1−/− mice and vehicle- and DAPT-treated C57/Bl6 mice to the controlled cortical impact model of TBI. In this model, an anesthetized animal has a 4 mm craniotomy performed on the central aspect of the left parietal bone. The impounder tip of the pneumatic injury device impacts the cortical surface at a moderate level (8.0 m/s velocity, 2 mm tissue deformation). This model induces both necrotic and apoptotic cell death, causing a brain lesion, and results in the development of behavioral deficits. Exposure to TBI resulted in accumulation of endogenous mouse A 2 within 1 day, with A 2 levels increased by almost 120% at day 3 before normalizing by day 7. As expected, the accumulation of A 2 corresponded with increased protein levels of APP, BACE1, and PS-1. We found that BACE1−/− and DAPT-treated mice had reduced motor deficits and decreased spatial memory impairments following trauma when compared to WT and Vehicle-treated mice. T2-weighted MRI analysis and histological assessment revealed that BACE−/− and DAPT treatment spared large areas of cortex and subcortical white matter tracks, reduced CA1 hippocampal neuron loss, and significantly reduced lesion size by 30% and >70%, respectively. Furthermore, DAPT treatment reduced endogenous A 2 levels by 25% following trauma. These data demonstrate that the APP secretases are important mediators of tissue loss following TBI, and that blocking either 2 - or gamma-secretases can ameliorate motor and cognitive deficits and reduce cell loss following experimental TBI. Thus, modulation of APP secretases may provide novel therapeutic targets for the treatment of TBI.