Identification of a new presenilin-dependent ζ-cleavage site within the transmembrane domain of amyloid precursor protein

gamma-Secretase cleavage of beta-amyloid precursor protein (APP) is crucial in the pathogenesis of Alzheimer disease, because it is the decisive step in the formation of the C terminus of beta-amyloid protein (Abeta). To better understand the molecular events involved in gamma-secretase cleavage of APP, in this study we report the identification of a new intracellular long Abeta species containing residues 1 - 46 (Abeta(46)), which led to the identification of a novel zeta-cleavage site between the known gamma- and epsilon-cleavage sites within the transmembrane domain of APP. Our data clearly demonstrate that the new zeta-cleavage is a presenilin-dependent event. It is also noted that the new zeta-cleavage site at Abeta46 is the APP717 mutation site. Furthermore, we show that the new zeta-cleavage is inhibited by gamma-secretase inhibitors known as transition state analogs but less affected by inhibitors known as non-transition state gamma-secretase inhibitors. Thus, the identification of Abeta(46) establishes a system to determine the specificity or the preference of the known gamma-secretase inhibitors by examining their effects on the formation or turnover of Abeta(46).