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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


Kwok, JB and Halliday, GM and Brooks, WS and Dolios, G and Laudon, H and Murayama, O and Hallupp, M and Badenhop, RF and Vickers, JC and Wang, R and Naslund, J and Takashima, A and Gandy, SE and Schofield, PR, Presenilin-1 Mutation L271V Results in Altered Exon 8 Splicing and Alzheimer's Disease with Non-cored Plaques and No Neuritic Dystrophy, Journal of Biological Chemistry, 278, (9) pp. 6748-6754. ISSN 0021-9258 (2003) [Refereed Article]

DOI: doi:10.1074/jbc.M211827200


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-1"exon8) 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-1"exon8 was overexpressed in an affected individual. Biochemical analysis of PS-1"exon8 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-1"exon8, 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-1"exon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Vickers, JC (Professor James Vickers)
ID Code:28341
Year Published:2003
Web of Science® Times Cited:47
Deposited By:Pathology
Deposited On:2003-08-01
Last Modified:2011-10-12

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