Amyloid Beta-Peptide Increases BACE1 Translation through the Phosphorylation of the Eukaryotic Initiation Factor-2α

Alzheimer's disease (AD) is tightly linked to oxidative stress since amyloid beta-peptide (Aβ) aggregates generate free radicals. Moreover, the aggregation of Aβ is increased by oxidative stress, and the neurotoxicity induced by the oligomers and fibrils is in part mediated by free radicals. Interestingly, it has been reported that oxidative stress can also induce BACE1 transcription and expression. BACE1 is the key enzyme in the cleavage of the amyloid precursor protein to produce Aβ, and the expression of this enzyme has been previously shown to be enhanced in the brains of Alzheimer's patients. Here, we have found that BACE1 expression is increased in the hippocampi from AD patients at both the early (Braak stage II) and late (Braak stage VI) stages of the disease as studied by immunohistochemistry and western blot. To address the role of Aβ and oxidative stress in the regulation of BACE1 expression, we have analyzed the effect of subtoxic concentrations of Aβ oligomers (0.25 μM) and H₂O₂ (10 mM) on a human neuroblastoma cell line. Firstly, our results show that Aβ oligomers and H₂O₂ induce an increase of BACE1 mRNA as we studied by qPCR. Regarding BACE1 translation, it is dependent on the phosphorylation of the eukaryotic initiation factor 2α (eIF2α), since BACE1 mRNA bears a 5'UTR that avoids its translation under basal conditions. BACE1 5'UTR contains four upstream initiating codons (uAUGs), and its translation is activated when eIF2α is phosphorylated. Consistently, we have obtained that Aβ oligomers and H₂O₂ increase the levels of BACE1 and p-eIF2α assayed by western blot and confocal microscopy. Our results suggest that Aβ oligomers increase BACE1 translation by phosphorylating eIF2α in a process that involves oxidative stress and conforms a pathophysiological loop, where the Aβ once aggregated favors its own production continuously by the increase in BACE1 expression as observed in AD patients.