Abstract #10: Amyloid Precursor Protein Secretases As Therapeutic Targets for Spinal Cord Injury

Abstract

Spinal cord injury (SCI) has a prevalence of 250,000 in the United States and an incidence of 12,000 cases per year. Secondary biochemical and physiological changes induced by trauma lead to delayed cell death, inflammation, glial scar formation, and impaired regeneration. Identification of secondary injury processes may lead to development of new therapies to limit tissue damage and improve functional outcome. Amyloid precursor protein (APP) is upregulated after SCI with a peak at 3 days. APP is sequentially cleaved by γ-secretase and β-secretase (BACE1) to produce Aβ, which is directly neurotoxic and also serves to activate microglia by releasing associated neuroinflammatory factors. We hypothesized that Aβ increases after SCI and contributes to secondary damage, and that treatment with a γ-secretase inhibitor will reduce inflammation, limit tissue loss, and reduce the functional deficits after injury. Here we show that Aβ increases at 1 day, peaks at 3 days, and begins to decrease at 7 days after spinal cord injury in mice. PS1, which is a component of γ-secretase, and BACE1 are upregulated after SCI. Moreover, treatment with a γ-secretase inhibitor (DAPT) reduces the production of Aβ after injury. These data suggest that γ-secretase inhibitors may have therapeutic benefit after SCI. Support This work was supported by grants from the Paralyzed Veterans of America ( PVA2685 ) and the National Institutes of Health ( 5R01NS054221-03 ).