Aneuploidy in the normal, Alzheimer's disease and ataxia-telangiectasia brain: differential expression and pathological meaning

Recently it has been suggested that the human brain contains aneuploid cells; however the nature and magnitude of neural aneuploidy in health and disease remain obscure. Here, we have monitored aneuploidy in the cerebral cortex of the normal, Alzheimer's disease (AD) and ataxia telangiectasia (AT) brain by molecular cytogenetic approaches scoring more than 480,000 neural cells. Using arbitrarily selected set of DNA probes for chromosomes 1, 7, 11, 13, 14, 17, 18, 21, X and Y we have determined the mean rate of stochastic aneuploidy per chromosome as 0.5% in the normal human brain (95%CI 0.2-0.7%; SD 0.2%). The overall proportion of aneuploid cells in the normal brain has been estimated at approximately 10%. In the AT brain, we observed a 2-to-5 fold increase of stochastic aneuploidy randomly affecting different chromosomes (mean 2.1%; 95%CI - 1.5-2.6%; SD 0.8%). The overall proportion of aneuploid cells in the brain of AT individuals was estimated at approximately 20-50%. Compared with sex- and age-matched controls, the level of stochastic aneuploidy in the AD brain was not significantly increased. However, a dramatic 10-fold increase of chromosome 21-specific aneuploidy (both hypoploidy and hyperploidy) was detected in the AD cerebral cortex (6-15% versus 0.8-1.8% in control). We conclude that somatic mosaic aneuploidy differentially contributes to intercellular genomic variation in the normal, AD and AT brain. Neural aneuploidy leading to altered cellular physiology may significantly contribute to the pathogenesis of neurodegenerative diseases. These data indicate neural aneuploidy to be a newly identified feature of neurodegenerative diseases, similar to other devastative disorders hallmarked by aneuploidy such as chromosome syndromes and cancer.