Cysteine proteases are the major β-secretase in the regulated secretory pathway that provides most of the β-amyloid in Alzheimer's disease: Role of BACE 1 in the constitutive secretory pathway

✍ Scribed by Vivian Y.H. Hook; Terry D. Reisine

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 410 KB
• Volume: 74
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.10784

✦ Synopsis

Abstract

This article focuses on β‐amyloid (Aβ) peptide production and secretion in the regulated secretory pathway and how this process relates to accumulation of toxic Aβ in Alzheimer's disease. New findings are presented demonstrating that most of the Aβ is produced and secreted, in an activity‐dependent manner, through the regulated secretory pathway in neurons. Only a minor portion of cellular Aβ is secreted via the basal, constitutive secretory pathway. Therefore, regulated secretory vesicles contain the primary β‐secretases that are responsible for producing the majority of secreted Aβ. Investigation of β‐secretase activity in regulated secretory vesicles of neuronal chromaffin cells demonstrated that cysteine proteases account for the majority of the β‐secretase activity. BACE 1 is present in regulated secretory vesicles but provides only a small percentage of the β‐secretase activity. Moreover, the cysteine protease activities prefer to cleave the wild‐type β‐secretase site, which is relevant to the majority of AD cases. In contrast, BACE 1 prefers to cleave the Swedish mutant β‐secretase site that is expressed in a minor percentage of the AD population. These new findings lead to a unifying hypothesis in which cysteine proteases are the major β‐secretases for the production of Aβ in the major regulated secretory pathway and BACE 1 is the β‐secretase responsible for Aβ production in the minor constitutive secretory pathway. These results indicate that inhibition of multiple proteases may be needed to decrease Aβ production as a therapeutic strategy for Alzheimer's disease. © 2003 Wiley‐Liss, Inc.