Abstract
BackgroundAlthough 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.ResultsExtended 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).ConclusionsAddressing 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.
Highlights
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
Using multiprobe/quantitative Fluorescence in situ hybridization (FISH) and interphase chromosome-specific multicolor banding (ICS-MCB) (Figure 1), we have assessed the rate of aneuploidy involving different chromosomes in postmortem brain tissues of 10 control and 10 AD patients analyzed in a double-blinded study
In the AD brain, the mean autosomal aneuploidy frequency was in a range of 0.86-1.22% and “autosomal” mean was 0.93% The mean frequency of X chromosome aneuploidy rates was 2.78%
Summary
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. We used a set of molecular cytogenetic techniques [23,24,25] providing high-resolution analysis of interphase chromosomes to detect genome variations manifesting at chromosomal level in small cell populations for a molecular neurocytogenetic analysis of the AD brain and control samples. Results Using multiprobe/quantitative FISH and interphase chromosome-specific multicolor banding (ICS-MCB) (Figure 1), we have assessed the rate of aneuploidy involving different chromosomes in postmortem brain tissues of 10 control and 10 AD patients analyzed in a double-blinded study. Scoring more than 140,000 cells in control samples and comparable amount of cells (140,000) in the AD brain has demonstrated aneuploidy rates (losses + gains) to vary in a wide range between chromosomes and individuals (Table 1).
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