Beyond the signaling effect role of amyloid-β42 on the processing of APP, and its clinical implications

Alzheimer's disease (AD) currently has over 6 million victims in the USA, alone. The recently FDA approved drugs for AD only provide mild, transient relief for symptoms without addressing underlying mechanisms to a significant extent. Basic understanding of the activities of the amyloid beta peptide (A beta) and associated proteins such as beta-site APP-cleaving enzyme 1 (BACE1) is necessary to develop effective medical responses to AD. Recently (Exper. Neurol. 2010. 221, 18-25), Tabaton et al. have presented a model of both non-pathological and pathological A beta activities and suggest potential therapeutic pathways based on their proposed framework of A beta acting as the signal that induces a kinase cascade, ultimately stimulating transcription factors that upregulate genes such as BACE1. We respond by presenting evidence of A beta's other activities, including protection against metal-induced reactive oxidizing species (ROS), modification of cholesterol transport, and potential activity as a transcription factor in its own right. We touch upon clinical implications of each of these functions and highlight the currently unexplored implications of our suggested novel function of A beta as a transcription factor. A beta appears to be a highly multi-functional peptide, and any or all of the pathways it engages in is a likely candidate for antiAD drug development. (C) 2010 Elsevier Inc. All rights reserved.