Alzheimer Aβ Peptide Induces Chromosome Mis-Segregation and Aneuploidy, Including Trisomy 21: Requirement for Tau and APP

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 A beta 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-3 beta, calpain, and Tau-dependent microtubule transport in the aneugenic activity of A beta. Furthermore, APP KO cells are resistant to the aneugenic activity of A beta, as they have been shown previously to be resistant to A beta-induced tau phosphorylation and cell toxicity. These results indicate that A beta-induced microtubule dysfunction leads to aneuploid neurons and may thereby contribute to the pathogenesis of AD.