Beyond the signaling effect role of amyloid-ß42 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 (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.
Lahiri
Debomoy K
DK
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dlahiri@iupui.edu
Maloney
Bryan
B
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D002784:Cholesterol
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