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: John B J Kwok, Glenda M Halliday, William S Brooks, Georgia Dolios, Hanna Laudon, Ohoshi Murayama, Marianne Hallupp, Renee F Badenhop, James Vickers, Rong Wang, Jan Naslund, Akihiko Takashima, Samuel E Gandy, Peter R Schofield
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 9 Pg. 6748-54 (Feb 28 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12493737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• DNA, Complementary
• Membrane Proteins
• PSEN1 protein, human
• Presenilin-1
• Protein Isoforms
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3

Topics

• Adult
• Aged
• Alzheimer Disease (genetics)
• Amyloid beta-Peptides (metabolism)
• Animals
• Blotting, Western
• Brain (metabolism, pathology)
• COS Cells
• DNA, Complementary (metabolism)
• Exons
• Female
• Gene Deletion
• Genes, Dominant
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Male
• Mass Spectrometry
• Membrane Proteins (genetics)
• Middle Aged
• Mutation
• Neurons (pathology)
• Pedigree
• Plasmids (metabolism)
• Precipitin Tests
• Presenilin-1
• Protein Isoforms
• RNA Splicing
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection