title: Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy.
abstract: The mutation L271V in exon 8 of the presenilin-1 (PS-1) gene was detected in an Alzheimer's disease pedigree. Neuropathological examination of affected individuals identified variant, large, non-cored plaques without neuritic dystrophy, reminiscent of cotton wool plaques. Biochemical analysis of L271V mutation showed that it increased secretion of the 42-amino acid amyloid-beta peptide, suggesting a pathogenic mutation. Analysis of PS-1 transcripts from the brains of two mutation carriers revealed a 17-50% increase in PS-1 transcripts with deletion of exon 8 (PS-1deltaexon8) compared with unrelated Alzheimer's disease brains. Exon trapping analysis confirmed that L271V mutation enhanced the deletion of exon 8. Western blots of brain lysates indicated that PS-1deltaexon8 was overexpressed in an affected individual. Biochemical analysis of PS-1deltaexon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-beta. Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3beta antibodies indicated that PS-1deltaexon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3beta, potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1deltaexon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, Sydney 2010, Australia.
authors.forename: John B J
authors.initials: JB
authors.lastname: Kwok
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.forename: William S
authors.initials: WS
authors.lastname: Brooks
authors.forename: Georgia
authors.initials: G
authors.lastname: Dolios
authors.forename: Hanna
authors.initials: H
authors.lastname: Laudon
authors.forename: Ohoshi
authors.initials: O
authors.lastname: Murayama
authors.forename: Marianne
authors.initials: M
authors.lastname: Hallupp
authors.forename: Renee F
authors.initials: RF
authors.lastname: Badenhop
authors.forename: James
authors.initials: J
authors.lastname: Vickers
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Jan
authors.initials: J
authors.lastname: Naslund
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Gandy
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005799:Genes, Dominant; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000473:pathology; D010375:Pedigree; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D053764:Presenilin-1; D020033:Protein Isoforms; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020033:Protein Isoforms; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3