title: The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue.
abstract: To gain insights into the significance of presenilins (PS) in the pathogenetic mechanisms of early-onset familial Alzheimer disease (FAD), we expressed cDNAs for wild-type PS2 and PS2 with the Volga German (N141I) mutation in cultured cells and then examined the metabolism of the transfected proteins and their effect on the C-terminal properties of secreted amyloid beta protein (A beta). PS2 was identified as a 50- to 55-kDa protein, which was cleaved to produce N-terminal fragments of 35-40 kDa and C-terminal fragments of 19-23 kDa. The Volga German (N141I) mutation did not cause any significant change in the metabolism of PS2. COS-1 cells doubly transfected with cDNAs for N141I mutant PS2 and human beta-amyloid precursor protein (betaAPP) or a C-terminal fragment thereof, as well as mouse Neuro2a neuroblastoma cells stably transfected with N141I mutant PS2 alone, secreted 1.5- to 10-fold more A beta ending at residues 42 (or 43) [A beta42(43)] compared with those expressing the wild-type PS2. These results strongly suggest that the PS2 mutation (N141I) linked to FAD alters the metabolism of A beta/betaAPP to foster the production of the form of A beta that most readily deposits in amyloid plaques. Thus, mutant PS2 may lead to AD by altering the metabolism of A beta/betaAPP.
authors.affiliation: Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tomita
authors.forename: K
authors.initials: K
authors.lastname: Maruyama
authors.forename: T C
authors.initials: TC
authors.lastname: Saido
authors.forename: H
authors.initials: H
authors.lastname: Kume
authors.forename: K
authors.initials: K
authors.lastname: Shinozaki
authors.forename: S
authors.initials: S
authors.lastname: Tokuhiro
authors.forename: A
authors.initials: A
authors.lastname: Capell
authors.forename: J
authors.initials: J
authors.lastname: Walter
authors.forename: J
authors.initials: J
authors.lastname: Grünberg
authors.forename: C
authors.initials: C
authors.lastname: Haass
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: K
authors.initials: K
authors.lastname: Obata
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary; D004797:Enzyme-Linked Immunosorbent Assay; D008040:Genetic Linkage; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D053766:Presenilin-2; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42); C098994:amyloid beta-protein (1-43)