Amyloid-β Production: Major Link Between Oxidative Stress and BACE1

Sequential endoproteolytic cleavages operated by the gamma-secretase and the beta-secretase (BACE1) on the beta-amyloid precursor protein result in the production of the beta-amyloid (A beta) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of A beta 42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of A beta accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS). Data reviewed here shed light on how A beta generation, oxidative stress, and secretase functions are intimately related in sporadic AD. According to our hypothesis, in sporadic AD, OS resulted from several cellular insults such as aging, hypoxia, hyperglycemia, and hypercholesterolemia-that are well-known risk factors for AD development-can determine a primary induction of gamma-secretase and BACE1. The loop proceeds with the generation of A beta 42 and its signaling to BACE1 transcription.