MOLECULAR DISSECTION OF DOMAINS IN MUTANT PRESENILIN-2 THAT MEDIATE OVERPRODUCTION OF AMYLOIDOGENIC FORMS OF AMYLOID-BETA PEPTIDES - INABILITY OF TRUNCATED FORMS OF PS2 WITH FAMILIAL ALZHEIMERS-DISEASE MUTATION TO INCREASE SECRETION OF A-BETA-42-ASTERISK

Mutations in presenilin (PS) 1 or PS2 genes account for the majority o f early-onset familial Alzheimer's disease, and these mutations have b een shown to increase production of species of amyloid beta peptide (A beta) ending at residue 42, i.e. the most amyloidogenic form of A bet a. To gain insight into the molecular mechanisms whereby mutant PS ind uces overproduction of A beta 42, we constructed cDNAs encoding mutant and/or truncated forms of PS2 and examined the secretion of A beta 42 hom COS or neuro2a cells transfected with these genes. Cells expressi ng full-length PS2 harboring both N141I and M239V mutations in the sam e polypeptide induced overproduction of A beta 42, although the levels of A beta 42 were comparable with those in cells engineered to expres s PS2 with one or the other of these PS2 mutations. In contrast, cells engineered to express partially truncated PS2 (eliminating the COOH-t erminal third of PS2 while retaining the endoproteolytic NH2-terminal fragment) and harboring a N141I mutation, as well as cells expressing COOH-terminal fragments of PS2, did not overproduce A beta 42, and the levels of A beta 42 were comparable with those in cells that expresse d full-length, wild-type PS2 or fragments thereof. These data indicate that: (i) the A beta 42-promoting effects of mutant PS2 proteins reac h the maximum level with a given single amino acid substitution tie. N 141I or M239V); and (ii) the expression of full-length mutant PS2 is r equired for the overproduction of A beta 42. Hence, cooperative intera ctions of NH2- and COOH-terminal fragments generated from full-length mutant PS2 may be important for the overproduction of A beta 42 that m ay underlie familial Alzheimer's disease.