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Borysov SI
,
Granic A
,
Padmanabhan J
,
Walczak CE
,
Potter H
.
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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.
Arendt,
Selective cell death of hyperploid neurons in Alzheimer's disease.
2010, Pubmed
Arendt,
Selective cell death of hyperploid neurons in Alzheimer's disease.
2010,
Pubmed
Bayer,
Intracellular accumulation of amyloid-Beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease.
2010,
Pubmed
Boeras,
Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy.
2008,
Pubmed
Borysov,
A novel role for Cdk1/cyclin B in regulating B-raf activation at mitosis.
2008,
Pubmed
,
Xenbase
Budde,
Analysis of microtubule polymerization in vitro and during the cell cycle in Xenopus egg extracts.
2006,
Pubmed
,
Xenbase
Chui,
Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.
1999,
Pubmed
Coulson,
What the evolution of the amyloid protein precursor supergene family tells us about its function.
2000,
Pubmed
Desai,
The use of Xenopus egg extracts to study mitotic spindle assembly and function in vitro.
1999,
Pubmed
,
Xenbase
Epstein,
The consequences of chromosome imbalance.
1990,
Pubmed
Ferhat,
Expression of the mitotic motor protein Eg5 in postmitotic neurons: implications for neuronal development.
1998,
Pubmed
,
Xenbase
Feuk,
Mutation screening of a haplotype block around the insulin degrading enzyme gene and association with Alzheimer's disease.
2005,
Pubmed
Funk,
Development of high-throughput screens for discovery of kinesin adenosine triphosphatase modulators.
2004,
Pubmed
Geller,
Chromosome missegregation and trisomy 21 mosaicism in Alzheimer's disease.
1999,
Pubmed
Glabe,
Structural classification of toxic amyloid oligomers.
2008,
Pubmed
Godin,
Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.
2010,
Pubmed
Goldstein,
Molecular motors: from one motor many tails to one motor many tales.
2001,
Pubmed
Granic,
Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP.
2010,
Pubmed
Hardy,
The amyloid hypothesis for Alzheimer's disease: a critical reappraisal.
2009,
Pubmed
Hardy,
A hundred years of Alzheimer's disease research.
2006,
Pubmed
Heald,
Microtubule-based motor function in mitosis.
1999,
Pubmed
Hebert,
Age-specific incidence of Alzheimer's disease in a community population.
1995,
Pubmed
Hsu,
Aneuploidy induction by mitotic arrestants in animal cell systems: possible mechanisms.
1985,
Pubmed
Iourov,
Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: differential expression and pathological meaning.
2009,
Pubmed
Kapoor,
Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5.
2000,
Pubmed
,
Xenbase
Kline-Smith,
Depletion of centromeric MCAK leads to chromosome congression and segregation defects due to improper kinetochore attachments.
2004,
Pubmed
,
Xenbase
Lazarov,
Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1.
2007,
Pubmed
Li,
Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation.
1997,
Pubmed
Lucarelli,
Association between presenilin-1 -48C/T polymorphism and Down's syndrome.
2004,
Pubmed
Mailhes,
Transient exposure to the Eg5 kinesin inhibitor monastrol leads to syntelic orientation of chromosomes and aneuploidy in mouse oocytes.
2004,
Pubmed
Mandelkow,
Tau in Alzheimer's disease.
1998,
Pubmed
Mazumdar,
Human chromokinesin KIF4A functions in chromosome condensation and segregation.
2004,
Pubmed
Migliore,
Preferential occurrence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients.
1999,
Pubmed
Migliore,
Susceptibility to chromosome malsegregation in lymphocytes of women who had a Down syndrome child in young age.
2006,
Pubmed
Migliore,
Spontaneous and induced aneuploidy in peripheral blood lymphocytes of patients with Alzheimer's disease.
1997,
Pubmed
Moorhead,
Chromosome studies of patients with Alzheimer disease.
1983,
Pubmed
Mosch,
Aneuploidy and DNA replication in the normal human brain and Alzheimer's disease.
2007,
Pubmed
Mucke,
High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
2000,
Pubmed
Noda,
KIF2 is a new microtubule-based anterograde motor that transports membranous organelles distinct from those carried by kinesin heavy chain or KIF3A/B.
1995,
Pubmed
Petersen,
Association between presenilin-1 polymorphism and maternal meiosis II errors in Down syndrome.
2000,
Pubmed
Pigino,
Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta.
2009,
Pubmed
Potter,
Review and hypothesis: Alzheimer disease and Down syndrome--chromosome 21 nondisjunction may underlie both disorders.
1991,
Pubmed
Rapoport,
Tau is essential to beta -amyloid-induced neurotoxicity.
2002,
Pubmed
Ringman,
Mosaicism for trisomy 21 in a patient with young-onset dementia: a case report and brief literature review.
2008,
Pubmed
Roberson,
Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model.
2007,
Pubmed
Rosenfeld,
Stepping and stretching. How kinesin uses internal strain to walk processively.
2003,
Pubmed
Rossi,
A new function of microtubule-associated protein tau: involvement in chromosome stability.
2008,
Pubmed
Schupf,
Increased risk of Alzheimer's disease in mothers of adults with Down's syndrome.
1994,
Pubmed
Snape,
Cell cycle aberrations in Alzheimer's disease: a novel therapeutic opportunity.
2009,
Pubmed
Stine,
In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.
2003,
Pubmed
Stokin,
Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease.
2005,
Pubmed
Takemura,
mRNA expression of KIF1A, KIF1B, KIF2, KIF3A, KIF3B, KIF4, KIF5, and cytoplasmic dynein during axonal regeneration.
1996,
Pubmed
Takeuchi,
Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss.
2000,
Pubmed
Tezapsidis,
Microtubular interactions of presenilin direct kinesis of Abeta peptide and its precursors.
2003,
Pubmed
Thomas,
Chromosome 17 and 21 aneuploidy in buccal cells is increased with ageing and in Alzheimer's disease.
2008,
Pubmed
Trippi,
Spontaneous and induced chromosome damage in somatic cells of sporadic and familial Alzheimer's disease patients.
2001,
Pubmed
Vernos,
Xklp1, a chromosomal Xenopus kinesin-like protein essential for spindle organization and chromosome positioning.
1995,
Pubmed
,
Xenbase
Walczak,
A model for the proposed roles of different microtubule-based motor proteins in establishing spindle bipolarity.
,
Pubmed
,
Xenbase
Walczak,
Mechanisms of mitotic spindle assembly and function.
2008,
Pubmed
,
Xenbase
Walczak,
XKCM1: a Xenopus kinesin-related protein that regulates microtubule dynamics during mitotic spindle assembly.
1996,
Pubmed
,
Xenbase
Wen,
The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.
2004,
Pubmed
Wolfe,
The secretases of Alzheimer's disease.
2003,
Pubmed
Wood,
CENP-E is a plus end-directed kinetochore motor required for metaphase chromosome alignment.
1997,
Pubmed
,
Xenbase
Yardimci,
The mitotic kinesin CENP-E is a processive transport motor.
2008,
Pubmed
,
Xenbase
Zhang,
Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease.
2007,
Pubmed
Zivković,
Premature centromere division of metaphase chromosomes in peripheral blood lymphocytes of Alzheimer's disease patients: relation to gender and age.
2010,
Pubmed