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 β peptide (Aβ) and associated proteins such as β-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 Aβ activities and suggest potential therapeutic pathways based on their proposed framework of Aβ 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 Aβ'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 Aβ as a transcription factor. Aβ 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.