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J. Biol. Chem., Vol. 278, Issue 9, 6748-6754, February 28, 2003

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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^*

From the ^a Garvan Institute of Medical Research, Darlinghurst, Sydney 2010, Australia, ^b Prince of Wales Medical Research Institute, Randwick 2031, Australia, ^c University of New South Wales, Sydney 2052, Australia, ^d Centre for Education and Research on Ageing, University of Sydney and Concord Repatriation General Hospital, Concord 2139, Australia, ^e Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, ^f Neurotec, Section of Experimental Geriatrics, Karolinska Institute, Stockholm S-141 86, Sweden, ^g Laboratory for Alzheimer's Disease, Brain Science Institute, Riken, Saitama 350-01, Japan, ^h Department of Pathology, University of Tasmania, Hobart, 7001, Australia, and ⁱ Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

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- 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-1exon8) 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-1exon8 was overexpressed in an affected individual. Biochemical analysis of PS-1exon8 in COS and BD8 cells indicate the splice isoform is not intrinsically active but interacts with wild-type PS-1 to generate amyloid-. Western blots of cell lysates immunoprecipitated with anti-Tau or anti-GSK-3 antibodies indicated that PS-1exon8, unlike wild-type PS-1, does not interact directly with Tau or GSK-3, potential modifiers of neuritic dystrophy. We postulate that variant plaques observed in this family are due in part to the effects of PS-1exon8 and that interaction between PS-1 and various protein complexes are necessary for neuritic plaque formation.

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