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Chromosome-specific accumulation of aneuploidy in the aging mouse brain.

ABSTRACT: Chromosomal aneuploidy, the gain or loss of whole chromosomes, is a hallmark of pathological conditions and a causal factor of birth defects and cancer. A number of studies indicate that aneuploid cells are present at a high frequency in the brain of mice and humans, suggesting that mosaic aneuploidies are compatible with normal brain function and prompting the question about their consequences. To explore the possible contribution of aneuploidy to functional decline and loss of cognitive functions during aging, we used a quantitative, dual-labeling interphase-fluorescence in situ hybridization approach to compare aneuploidy levels of chromosomes 1, 7, 14, 15, 16, 18, 19 and Y in the cerebral cortex of 4- and 28-month-old mice. We show that aneuploidy accumulates with age in a chromosome-specific manner, with chromosomes 7, 18 and Y most severely affected, i.e. up to 9.8% of non-neuronal brain nuclei in 28-month-old animals for chromosome 18. While at early age, both neuronal and glial cells are affected equally, the age-related increase was limited to the non-neuronal nuclei. No age-related increase in aneuploidy was observed in the cerebellum or in the spleen of the same animals. Extrapolating the average frequencies of aneuploidy from the average over 8 chromosomes to all 20 mouse chromosomes would indicate an almost 50% aneuploidy frequency in aged mouse brain. Such high levels of genome instability could well be a factor in age-related neurodegeneration.

SUBMITTER: Faggioli F

PROVIDER: S-EPMC3510757 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Chromosome-specific accumulation of aneuploidy in the aging mouse brain.

Faggioli Francesca F Wang Tao T Vijg Jan J Montagna Cristina C

Human molecular genetics 20120906 24

Chromosomal aneuploidy, the gain or loss of whole chromosomes, is a hallmark of pathological conditions and a causal factor of birth defects and cancer. A number of studies indicate that aneuploid cells are present at a high frequency in the brain of mice and humans, suggesting that mosaic aneuploidies are compatible with normal brain function and prompting the question about their consequences. To explore the possible contribution of aneuploidy to functional decline and loss of cognitive functi ...[more]

PMID: 22962300

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Project description:BackgroundThe role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer's disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase ? (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age.ResultsWe crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect A? synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that A?42 levels along with A?42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated A? production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major A? clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei.ConclusionsOverall, our results implicate synergism between the effects of the PolgA D257A mutation and A? in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of A?.

Dataset Information

Chromosome-specific accumulation of aneuploidy in the aging mouse brain.

Publications

Chromosome-specific accumulation of aneuploidy in the aging mouse brain.

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