Effect of Ischemic Neuronal Insults on Amyloid Precursor Protein Processing

Background: In spite of the different pathogenesis and exclusive respect in the diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD), recent epidemiological and pathological studies indicates that ischemic stroke have an important role in the pathogenesis of both VaD and AD. However,the association of ischemic stroke and AD on the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insult on the regulation of amyloid precursor protein (APP) processing. Methods: We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD) to evaluate the effect of ischemic insult on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line, SH-SY5Y, and primary cultured cells of Tg2576 APP transgenic mouse. Results: Ischemic insult significantly increased the beta amyloid (A) production in the primary cultured cells of Tg2576 APP transgenic mice (p- secretase, was markedly increased in the early stage of ischemic insult (up to 2 hours of OGD, p-site cleavage enzyme (BACE) and BACE activity were not significantly different between the group of schemic insult and control. By contrast, the activity of -secretase was significantly increased after 4 hours of ischemic insult, as compared to controls. Conclusions: This study demonstrates that the ischemic neuronal insults increase the production of A via activation of the amyloidogenic pathway, which may link the role of ischemic insults to the pathogenesis of AD.