University Of Tasmania

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Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy

journal contribution
posted on 2023-05-16, 14:40 authored by Kwok, JB, Halliday, GM, Brooks, WS, Dolios, G, Laudon, H, Murayama, O, Hallupp, M, Badenhop, RF, James VickersJames Vickers, Wang, R, Naslund, J, Takashima, A, Gandy, SE, Schofield, PR
The mutation L271V in exon 8 of the presenilin-1 (PS-i) 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-β 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-1Δexon8) 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-1Δexon8 was overexpressed in an affected individual. Biochemical analysis of PS-1Δexon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-β. Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3β antibodies indicated that PS-1Δexon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3β, potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1Δexon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.


Publication title

Journal of Biological Chemistry










Tasmanian School of Medicine


American Society for Biochemistry and Molecular Biology, Inc

Place of publication

Bethesda, USA

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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