Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

Background: beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a membrane-bound aspartyl protease that initiates amyloid beta-protein (A beta) generation. Aberrant elevation of BACE1 levels in brains of Alzheimer's disease (AD) patients may involve A beta. In the present study, we used a neuron culture model system to investigate the effects of A beta on BACE1 expression as well as the underlying mechanisms. Results: Rat primary cortical neurons were treated with relatively low concentrations (2.5 mu M) of A beta 42 oligomers (A beta-O) or fibrils (A beta-F) for 2-3 days. A beta-O induced a significant increase in protein levels of BACE1, while A beta-F only had a marginal effect. Levels of amyloid precursor protein (APP) and the major a-secretase, ADAM10, remained unaltered upon treatment with both types of A beta. A beta-O treatment resulted in activation of eIF2a and caspase 3 in a time-dependent manner, with no changes in the endoplasmic reticulum (ER) stress marker, GRP78, indicating that a typical ER stress response is not induced under our experimental conditions. Furthermore, A beta-O did not affect BACE1 mRNA expression but augmented the levels of exogenous BACE1 expressed via recombinant adenoviruses, indicating regulation of BACE1 protein expression, not at the transcriptional or translational but the post-translational level. Immunocytochemical analysis revealed that A beta-O causes a significant increase in BACE1 immunoreactivity in neurites (both axons and dendrites), but not soma of neurons; this change appears relevant to the mechanism of A beta-O-induced BACE1 elevation, which may involve impairment of BACE1 trafficking and degradation. In contrast, A beta-O had no effect on APP immunoreactivity. Conclusion: Our results collectively suggest that A beta oligomers induce BACE1 elevation via a post-translational mechanism involving its altered subcellular distribution in neurons, which possibly triggers a vicious cycle of A beta generation, thus contributing to the pathogenetic mechanism of AD.