Alzheimer Aβ disrupts the mitotic spindle and directly inhibits mitotic microtubule motors

Sergiy I. Borysov, Antoneta Granic, Jaya Padmanabhan, Claire E. Walczak, Huntington Potter

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Chromosome mis-segregation and aneuploidy are greatly induced in Alzheimer disease and models thereof by mutant forms of the App and pS proteins and by their product, the Aβ peptide. Here we employ human somatic cells and Xenopus egg extracts to show that Aβ impairs the assembly and maintenance of the mitotic spindle. Mechanistically, these defects result from Aβ's inhibition of mitotic motor kinesins, including Eg5, KIF4A and MCAK. In vitro studies show that oligomeric Aβ directly inhibits recombinant MCAK by a noncompetitive mechanism. In contrast, inhibition of Eg5 and KIF4A is competitive with respect to both ATP and microtubules, indicating that Aβ interferes with their interactions with the microtubules of the mitotic spindle. Consistently, increased levels of polymerized microtubules or of the microtubule stabilizing protein tau significantly decrease the inhibitory effect of Aβ on Eg5 and KIF4A. together, these results indicate that by disrupting the interaction between specific kinesins and microtubules and by exerting a direct inhibitory effect on the motor activity, excess Aβ deregulates the mechanical forces that govern the spindle and thereby leads to the generation of defective mitotic structures. the resulting defect in neurogenesis can account for the over 30% aneuploid/ hyperploid, degeneration-prone neurons observed in Alzheimer disease brain. the finding of mitotic motors including Eg5 in mature post-mitotic neurons implies that their inhibition by Aβ may also disrupt neuronal function and plasticity.

Original languageEnglish (US)
Pages (from-to)1397-1410
Number of pages14
JournalCell Cycle
Volume10
Issue number9
DOIs
StatePublished - May 1 2011

Keywords

  • Alzheimer disease
  • Amyloid
  • Aneuploidy
  • Eg5
  • KIF4A
  • MCAK

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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