Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy
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||Kwok, J. B.;Halliday, G. M.;Brooks, W. S.;Dolios, G.;Laudon, H.;Murayama, O.;Hallupp, M.;Badenhop, R. F.;Vickers, J.;Wang, R.;Naslund, J.;Takashima, A.;Gandy, S. E.;Schofield, P. R. :|
|Publisher Name||JOURNAL OF BIOLOGICAL CHEMISTRY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12493737|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/1686|