Metabolic processing of the amyloid precursor protein -- new pieces of the Alzheimer's puzzle.

Alzheimer's disease (AD) continues to be a daunting and costly challenge for research, medicine, and society. AD pathologies point toward the involvement of metabolic fragments of the amyloid precursor protein (APP) in the pathogenesis of the disease. Through sequential enzymatic processing, APP is metabolized into several potential polypeptides, including the toxic amyloid-β (Aβ) peptide. Though great progress has been made in understanding the mechanism of conventional metabolic processing of APP to yield products such as Aβ, AD remains unpreventable and irreversible at any stage. Recent new reports provide data that add both complexity to the issue and new hope for potential avenues of therapeutic intervention. Novel metabolic processing events such as delta-secretase and eta-secretase have been revealed that generate previously uncharacterized APP metabolic fragments with the potential to participate in AD pathogenesis. Additionally, enzymes known to act in other metabolic pathways, such as meprin β, have been found to cleave APP to yield products known to participate in AD pathologies. This review provides an overview of current knowledge of conventional and novel APP processing.