Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury

Amyloid-beta (A beta) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by beta (Bace1) and gamma-secretases. The accumulation and aggregation of A beta as amyloid plaques is the hallmark pathology of Alzheimer's disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of A beta after injury is not well understood, several studies have reported a negative correlation between A beta formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and gamma-secretase), and A beta are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of All after SCI, we reduced or inhibited A beta in vivo through pharmacological (using DAFT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for A beta after SCI. (C) 2014 Elsevier B.V. All rights reserved.