Beyond the signaling effect role of amyloid-ß42 on the processing of APP, and its clinical implications

Abstract

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 (Abeta) 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 Abeta activities and suggest potential therapeutic pathways based on their proposed framework of Abeta 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 Abeta'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 Abeta as a transcription factor. Abeta 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.

Fig. 1. Self–regulation of Aβ cleavage from AβPP through the BACE1 gene promoter and therapeutic implications

A) Intranuclear Aβ peptide would function as a transcription factor, upregulating BACE1 gene transcription. This would stimulate production of BACE1 mRNA as a template for BACE1 protein production. BACE1 would cleave AβPP at the β–cleavage site. When this is followed by γ–cleavage, extracellular Aβ is released. Aβ would then enter the cell through currently–uncharacterized receptor(s) that could include FPR2, insulin receptor, or NMDA receptors (Verdier, et al., 2004). Once within the cell, Aβ would then be transported into the nucleus to renew the cycle. B) Under pathogenic conditions, Aβ levels would have been stimulated to increase BACE1 transcription to the extent that normal Aβ clearance pathways, such as IDE, would fall behind. Additional Aβ would be transported into the cell, to stimulate increased BACE1 transcription, resulting in an uncontrolled positive feedback loop. C) Therapeutic blockage of Aβ–BACE1 promoter interaction by sequence specific siRNA or antisense DNA oligomers would result in reduced BACE1 gene transcription, theoretically permitting Aβ clearance mechanisms to catch up to production. Reduced production would restore a state similar to pre disease levels.