X chromosome aneuploidy in the Alzheimer’s disease brain

Abstract

Background: Although the link between brain aging and Alzheimer's disease (AD) is a matter of debate, processes hallmarking cellular and tissue senescence have been repeatedly associated with its pathogenesis. Here, we have studied X chromosome aneuploidy (a recognized feature of aged cell populations) in the AD brain.Results: Extended molecular neurocytogenetic analyses of X chromosome aneuploidy in 10 female AD as well as 10 age and sex matched female control postmortem brain samples was performed by multiprobe/quantitative FISH. Additionally, aneuploidy rate in the brain samples of 5 AD and as 5 age and sex matched control subjects were analyzed by interphase chromosome-specific multicolor banding (ICS-MCB). Totally, 182,500 cells in the AD brain and 182,500 cells in the unaffected brain were analyzed. The mean rate of X chromosome aneuploidy in AD samples was approximately two times higher than in control (control: mean -1.32%, 95% CI 0.92-1.71%; AD: mean -2.79%, 95% CI 1.88-3.69; P = 0.013). One AD sample demonstrated mosaic aneuploidy of chromosome X confined to the hippocampus affecting about 10% of cells. ICS-MCB confirmed the presence of X chromosome aneuploidy in the hippocampal tissues of AD brain (control: mean -1.74%, 95% CI 1.38-2.10%; AD: mean -4.92%, 95% CI 1.14-8.71; P < 0.001). Conclusions: Addressing X chromosome number variation in the brain, we observed that somatically acquired (post-zygotic) aneuploidy causes large-scale genomic alterations in neural cells of AD patients and, therefore, can be involved in pathogenesis of this common neurodegenerative disorder. In the context of debates about possible interplay between brain aging and AD neurodegeneration, our findings suggest that X chromosome aneuploidy can contribute to both processes. To this end we conclude that mosaic aneuploidy in the brain is a new non-heritable genetic factor predisposing to AD.

Aneuploidy in Lewy body diseases

“…Increased expression of cyclindependent kinase 5 in the rat SN induces neuron death (Henchcliffe and Burke, 1997), and hyperploidy is recognized as a separate mechanism for cell loss in AD (Arendt et al, 2010;Herrup, 2012;Yurov et al, 2014). In the present study, hyperploidy in the cortex and hippocampus was associated with AD pathology rather than neuronal loss.…”

Chromosomal instability: A common feature and a therapeutic target of cancer

“…Aneuploidy is also thought to be involved in the development of neurodegenerative diseases such as Alzheimer's disease [39][40][41]. Aneuploidy-induced proteotoxic stress is possibly implicated in the pathogenesis, because it is recognized that protein misfolding is associated with neurodegeneration.…”

Does Aneuploidy in the Brain Play a Role in Neurodegenerative Disease?

“…But a speciic increase in chromosome 21 aneuploidy in neurons of AD brain samples was identiied, of which 60% where gains and 40% loss of chromosome 21 [64]. On the other hand, in a recent study, a twofold increase in X chromosome aneuploidy was found in AD neurons when compared to age matched controls [65]. To summarize, although again the rates of aneuploidy and which chromosomes are afected difer between studies, the overall trends suggest that aneuploidy might be increased in AD [66].…”