C terminus of presenilin is required for overproduction of amyloidogenic Abeta 42 through stabilization and endoproteolysis of presenilin

Mutations in presenilin (PS) genes cause early onset familial Alzheimer's d isease (FAD) by increasing production of the amyloidogenic form of amyloid beta peptides ending at residue 42 (A beta 42). To identify a PS subdomain responsible for overproduction of A beta 42, we analyzed neuro2a cell lines expressing modified forms of PS2 that harbor an N141I FAD mutation. Deleti on or addition of amino acids at the C terminus and Ile448 substitution in PS2 with the N141I FAD mutation abrogated the increase in Ab42 secretion, a nd Ab42 overproduction was dependent on the stabilization and endoproteolys is of PS2. The same C-terminal modifications in PS1 produced similar effect s. Hence, we suggest that the C terminus of PS plays a crucial role in the overproduction of A beta 42 through stabilization of endoproteolytic PS der ivatives and that these derivatives may be the pathologically active specie s of PS that cause FAD.