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

Item Type:	Refereed Article
Research Division:	Medical and Health Sciences
Research Group:	Neurosciences
Research Field:	Neurology and Neuromuscular Diseases
Objective Division:	Health
Objective Group:	Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:	Nervous System and Disorders
UTAS Author:	Vickers, JC (Professor James Vickers)
ID Code:	28341
Year Published:	2003
Web of Science® Times Cited:	39
Deposited By:	Pathology
Deposited On:	2003-08-01
Last Modified:	2011-10-12
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