C terminus of presenilin is required for overproduction of amyloidogenic Aβ342 through stabilization and endoproteolysis of presenilin

Mutations in presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD) by increasing production of the amyloidogenic form of amyloid β peptides ending at residue 42 (Aβ42). To identify a PS subdomain responsible for overproduction of Aβ42, we analyzed neuro2a cell lines expressing modified forms of PS2 that harbor an N1411 FAD mutation. Deletion or addition of amino acids at the C terminus and Ile448 substitution in PS2 with the N1411 FAD mutation abrogated the increase in Aβ42 secretion, and Aβ42 overproduction was de- pendent on the stabilization and endoproteolysis of PS2. The same C-terminal modifications in PS1 produced similar effects. Hence, we suggest that the C terminus of PS plays a crucial role in the overproduction of Aβ42 through stabilization of endoproteolytic PS derivatives and that these derivatives may be the pathologically active species of PS that cause FAD.