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Alternative pathways for production of β-amyloid peptides of Alzheimer's disease

Abstract This highlight article describes three Alzheimer's disease (AD) studies presented at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms for producing neurotoxic β-amyloid (Aβ) peptides. One group described the poor kinetics of BACE 1 for cleaving the wild-type (WT) β-secretase site of APP found in most AD patients. They showed that cathepsin D displays BACE 1-like specificity and cathepsin D is 280-fold more abundant in human brain than BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the WT β-secretase site, they suggested continuing the search for additional β-secretase(s). The second group reported cathepsin B as an alternative β-secretase possessing excellent kinetic efficiency and specificity for the WT β-secretase site. Significantly, inhibitors of cathepsin B improved memory, with reduced amyloid plaques and decreased Aβ(40/42) in brains of AD animal models expressing amyloid precursor protein containing the WT β-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Aβ. Results showed that cathepsin B, but not BACE 1, efficiently cleaves the WT β-secretase isoaspartate site. Furthermore, cyclization of N-terminal Glu by glutaminyl cyclase generates highly amyloidogenic pGluAβ(3–40/42). These presentations suggest cathepsin B and glutaminyl cyclase as potential new AD therapeutic targets.