Alzheimer Aβ Peptide Induces Chromosome Mis-Segregation and Aneuploidy, Including Trisomy 21: Requirement for Tau and APP
Open Access
- 15 February 2010
- journal article
- research article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 21 (4), 511-520
- https://doi.org/10.1091/mbc.e09-10-0850
Abstract
Both sporadic and familial Alzheimer's disease (AD) patients exhibit increased chromosome aneuploidy, particularly trisomy 21, in neurons and other cells. Significantly, trisomy 21/Down syndrome patients develop early onset AD pathology. We investigated the mechanism underlying mosaic chromosome aneuploidy in AD and report that FAD mutations in the Alzheimer Amyloid Precursor Protein gene, APP, induce chromosome mis-segregation and aneuploidy in transgenic mice and in transfected cells. Furthermore, adding synthetic Aβ peptide, the pathogenic product of APP, to cultured cells causes rapid and robust chromosome mis-segregation leading to aneuploid, including trisomy 21, daughters, which is prevented by LiCl addition or Ca2+ chelation and is replicated in tau KO cells, implicating GSK-3β, calpain, and Tau-dependent microtubule transport in the aneugenic activity of Aβ. Furthermore, APP KO cells are resistant to the aneugenic activity of Aβ, as they have been shown previously to be resistant to Aβ-induced tau phosphorylation and cell toxicity. These results indicate that Aβ-induced microtubule dysfunction leads to aneuploid neurons and may thereby contribute to the pathogenesis of AD.This publication has 88 references indexed in Scilit:
- Structure of the complex of a mitotic kinesin with its calcium binding regulatorProceedings of the National Academy of Sciences of the United States of America, 2009
- The Mechanism of Ca2+-Dependent Regulation of Kinesin-Mediated Mitochondrial MotilityCell, 2009
- Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway HypothesisNeuron, 2008
- Aβ Oligomers Induce Neuronal Cell Cycle Events in Alzheimer's DiseaseJournal of Neuroscience, 2008
- Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidyNeurobiology of Aging, 2008
- Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1Journal of Neuroscience, 2007
- Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's diseaseExperimental Neurology, 2007
- Aβ induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597–624)The FASEB Journal, 2006
- Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of PathogenesisScience, 2003
- Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitroNature, 1995