The influence of endoproteolytic processing of familial Alzheimer's disease presenilin 2 on A beta 42 amyloid peptide formation

Mutant presenilins (PS) contribute to the pathogenesis of familial Alzheime r's disease (FAD) by enhancing the production of A beta 42 from beta-amyloi d precursor protein. Presenilins are endoproteolytically processed to N-ter minal and C-terminal fragments, which together form a stable 1:1 complex. W e have mapped the cleavage site in the PS2 protein by direct sequencing of its C-terminal fragment isolated from mouse liver. Three different N-termin al residues were identified starting at Val-299, Thr-301, and Leu-307 that correspond closely to the previously described N termini of the C-terminal fragment of human PS1, Mutational analysis of the PS2 cleavage site indicat es that the principal endoproteolytic cleavage occurs at residues Met-298/V al-299 and that the N terminus is subsequently modified by secondary proteo lytic cleavages. We have generated cleavage defective PS2 constructs, which accumulate exclusively as full-length polypeptides in transfected Neuro2a cells. Functional analysis of such cleavage defective PS2 carrying the FAD mutation Asn-141 --> Ile showed that its A beta 42 producing activity was s trongly reduced compared with cleavage-competent FAD PS2, In contrast, clea vage defective PS2 was active in rescuing the egg-laying defect of a sel-12 mutant in Caenorhabditis elegans. We conclude that PS2 endoproteolytic cle avage is not an absolute requirement for its activities but may rather sele ctively enhance or stabilize its functions.