Increased beta-secretase activity and expression in rats following transient cerebral ischemia

The aberrant proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretases is key to amyloid plaque formation in Alzheimer's disease (AD). Identification of an aspartyl protease as the beta-secretase (beta-site APP cleaving enzyme, BACE) involved in APP processing provides a pharmaceutical target for potential AD treatment. In the present studies, we demonstrate that transient cerebral ischemia in female rats caused a 30% increase in beta-secretase activity. alpha-Secretase activity did not increase significantly. We examined protein levels of BACE1, and its analogue BACE2, in ischemic brain extracts. BACE1 protein levels increased 67%, while BACE2 protein level did not change after such a transient ischemia. Immunohistochemical studies demonstrated that BACE1 protein was increased in the ischemic neocortex, when compared with its contralateral cortex. Further, colocalization assessment indicated that BACE1 strongly associated with staining for the apoptotic marker, TUNEL. These results may partially explain epidemiological study, which demonstrate a higher incidence of dementia after stroke. Further, our results support the hypothesis that apoptosis and aberrant APP processing are correlated events in AD brain, and suggest that inhibition of BACE may have a therapeutic effect in the prevention of dementia after stroke recovery.