Are γ-secretase and its associated Alzheimer's disease γ problems?

Presenilins (PS1 and PS2) and the amyloid-beta precursor protein (A beta PP) are the only known proteins as causing monogenic Alzheimer's disease. A beta PP is not the unique substrate of the gamma-secretase complex. Presenilins are also implicated in the processing of Notch, an important developmental protein, which is thought to compete directly with A beta PP for cleavage by gamma-secretase. In the context of cleavages in alpha, beta and gamma and with the recent three-dimensional models of gamma-secretase complex, a kinetic study of the sequential proteolysis of A beta PP prompts us to think the possible existence of two entrance sites for substrate with only one exit site, a configuration depicting a lower-case gamma letter. The quantitative distribution of the cleavage products by the gamma-secretase, mainly A beta(40), A beta(42) and A beta(43), could be explained in the context of this hypothesis. Based on published results in the literature and the analyses of A beta PP C99 fragment, highly abundant in Down's syndrome patients, we propose that beta- and gamma-secretases can function as a supra-enzyme complex where A beta PP substrate might be attached to the gamma-secretase complex before beta cleavage takes place. Different studies point that a small peptide sequence, showing homology in presenilins and A beta PP, plays a pivotal role and that minor alterations in the sequence of A beta PP protein limit the formation of C99 and also of A beta(40) and A beta(42). The model proposed could be of importance in future studies aimed at understanding the specific events involved in course of Alzheimer disease pathophysiology and also at studying of formation/deterioration of memory. (C) 2011 Elsevier Ltd. All rights reserved.