Putting presenilins centre stage

Abstract

Genetic analysis of autosomal dominant Alzheimer disease has identified the amyloid precursor protein (APP) and the presenilins as its pathogenic loci (Rogaeva, 2002). APP is normally cleaved by γ‐secretase into the APP intracellular domain (AICD) and the 40‐residue amyloid β peptide (Aβ40) or, less frequently, the 42‐residue Aβ42. Analyses of blood plasma from mutation carriers shows that all of the pathogenic mutations cause an increase in the Aβ42/Aβ40 ratio, suggesting that they alter the position of the γ‐secretase cleavage of APP (Scheuner et al , 1996; Haass & Selkoe, 1993). Gene‐ablation studies and focused mutagenesis experiments by De Strooper, Wolfe and their colleagues (De Strooper et al , 1998; Wolfe et al , 1999) shows that the presenilins—along with other accessory proteins (Edbauer et al , 2003)—form the γ‐secretase complex. This work is a good example of how genetic analysis can give direct mechanistic insight into the pathogenesis of …