title: Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy.
abstract: Mutations in the presenilin 1 gene cause most early onset familial Alzheimer's disease (FAD). Here, we report that a defect in the cell cycle - improper chromosome segregation - can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: (1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knocking mice are aneuploid by metaphase chromosome analysis and in situ hybridization. (2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 h, including trisomy 21. (3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.
authors.affiliation: Department of Molecular Medicine and Suncoast Gerontology Center, University of South Florida, College of Medicine, Tampa, FL 33612, USA.
authors.forename: Debrah I
authors.initials: DI
authors.lastname: Boeras
authors.forename: Antoneta
authors.initials: A
authors.lastname: Granic
authors.forename: Jaya
authors.initials: J
authors.lastname: Padmanabhan
authors.forename: Nichole C
authors.initials: NC
authors.lastname: Crespo
authors.forename: Amyn M
authors.initials: AM
authors.lastname: Rojiani
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D000782:Aneuploidy; D000818:Animals; D002478:Cells, Cultured; D020090:Chromosome Segregation / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D008715:Methionine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics*; D008941:Spindle Apparatus / Q000473:pathology; D013154:Spleen / Q000166:cytology; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
chemical_list: D010982:Platelet-Derived Growth Factor; D053764:Presenilin-1; D008715:Methionine; D014633:Valine; D008239:Lysine