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

Cell Cycle. 2011 May 1;10(9):1397-410. doi: 10.4161/cc.10.9.15478. Epub 2011 May 1.

Abstract

Chromosome mis-segregation and aneuploidy are greatly induced in Alzheimer's disease and models thereof by mutant forms of the APP and PS proteins and by their product, the Ab 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 Ab 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 Ab may also disrupt neuronal function and plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / physiology
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Cells, Cultured
  • Humans
  • Kinesins / antagonists & inhibitors
  • Kinesins / physiology
  • Mitosis / physiology*
  • Molecular Motor Proteins / antagonists & inhibitors*
  • Molecular Motor Proteins / physiology*
  • Oocytes / cytology
  • Oocytes / physiology
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology
  • Peptide Fragments / toxicity*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / toxicity
  • Spindle Apparatus / metabolism*
  • Spindle Apparatus / pathology
  • Xenopus

Substances

  • Amyloid beta-Peptides
  • KIF11 protein, human
  • KIF2C protein, human
  • Molecular Motor Proteins
  • Peptide Fragments
  • Recombinant Proteins
  • amyloid beta-protein (1-42)
  • KIF4A protein, human
  • Kinesins