title: Presenilin 1 mutations linked to familial Alzheimer's disease increase the intracellular levels of amyloid beta-protein 1-42 and its N-terminally truncated variant(s) which are generated at distinct sites.
abstract: Mutations in the presenilin genes PS1 and PS2 cause the most common form of early-onset familial Alzheimer's disease. The influence of PS1 mutations on the generation of endogenous intracellular amyloid beta-protein (A beta) species was assessed using a highly sensitive immunoblotting technique with inducible mouse neuroblastoma (Neuro 2a) cell lines expressing the human wild-type (wt) or mutated PS1 (M146L or delta exon 10). The induction of mutated PS1 increased the intracellular levels of two distinct A beta species ending at residue 42 that were likely to be A beta1-42 and its N-terminally truncated variant(s) A beta x-42. The induction of mutated PS1 resulted in a higher level of intracellular A beta1-42 than of intracellular A beta x-42, whereas extracellular levels of A beta1-42 and A beta x-42 were increased proportionally. In addition, the intracellular generation of these A beta42 species in wt and mutated PS1-induced cells was completely blocked by brefeldin A, whereas it exhibited differential sensitivities to monensin: the increased accumulation of intracellular A beta x-42 versus inhibition of intracellular A beta1-42 generation. These data strongly suggest that A beta x-42 is generated in a proximal Golgi, whereas A beta1-42 is generated in a distal Golgi and/or a post-Golgi compartment. Thus, it appears that PS1 mutations enhance the degree of 42-specific gamma-secretase cleavage that occurs in the normal beta-amyloid precursor protein processing pathway (a) in the endoplasmic reticulum or the early Golgi apparatus prior to beta-secretase cleavage or (b) in the distinct sites where A beta x-42 and A beta1-42 are generated.
authors.affiliation: Department of Dementia Research, National Institute for Longevity Sciences, Obu, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sudoh
authors.forename: Y
authors.initials: Y
authors.lastname: Kawamura
authors.forename: S
authors.initials: S
authors.lastname: Sato
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: T C
authors.initials: TC
authors.lastname: Saido
authors.forename: F
authors.initials: F
authors.lastname: Oyama
authors.forename: Y
authors.initials: Y
authors.lastname: Sakaki
authors.forename: H
authors.initials: H
authors.lastname: Komano
authors.forename: K
authors.initials: K
authors.lastname: Yanagisawa
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020126:Brefeldin A; D003517:Cyclopentanes / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008040:Genetic Linkage; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D018942:Macrolides; D008565:Membrane Proteins / Q000235:genetics* / Q000494:pharmacology*; D051379:Mice; D008985:Monensin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000378:metabolism; D053764:Presenilin-1; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D003517:Cyclopentanes; D018942:Macrolides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D020126:Brefeldin A; D008985:Monensin