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

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