β‐Site APP cleaving enzyme up‐regulation induced by 4‐hydroxynonenal is mediated by stress‐activated protein kinases pathways

Abstract 4‐Hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, up‐regulates expression of the β‐site APP cleaving enzyme (BACE‐1), an aspartyl protease responsible for the β‐secretase cleavage of amyloid precursor protein (AβPP), and results in increased levels of amyloid β (Aβ) peptide. The mechanisms underlying this remain unclear but are of fundamental importance because prevention of BACE‐1 up‐regulation is viewed as an important therapeutic strategy. In this study, we exposed NT 2 neurons to a range of HNE concentrations (0.5–5 µ m ) that elicited an up‐regulation of BACE‐1 expression, a significant increase in intracellular and secreted levels of Aβ peptides as well as apoptosis involving poly‐ADP ribose polymerase cleavage and activation of caspase 3. To delineate the molecular events involved in HNE‐mediated BACE‐1 activation, we investigated the involvement of stress‐activated protein kinases (SAPK), signal transducers and activators of transcription (STAT) and serine–threonine kinase B/phosphatidylinositol phosphate 3 kinase (Akt/PtdIns3K). Using specific pharmacological inhibitors, our results show that activation of c‐Jun N‐terminal kinases and p38 MAPK. , but not STAT or Akt/PtdIns3K, pathways mediate the HNE‐dependent up‐regulation of BACE‐1 expression. Therefore, HNE, an oxidative stress mediator detected in vivo in the brains of Alzheimer's disease patients, may play a pathogenetic role in Alzheimer's disease by selectively activating SAPK pathways and BACE‐1 that regulate the proteolytic processing of AβPP.