Somatic Mosaicism of Chromosome 21 in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder primarily characterised by memory loss due to neural atrophy. AD pathology is typified by Tau tangles and senile plaques. The plaques are aggregations of beta-sheets of the amyloid beta peptide (Aβ). The Aβ peptide is produced from the amyloid precursor protein which is transcribed from the APP gene on chromosome 21. The hypothesis tested in this project was that increased dosage of the APP gene due to somatic mosaicism of trisomy 21 may contribute to AD. This dosage effect has been previously observed in Down’s syndrome (DS), a condition caused by three copies of chromosome 21, and which has a much higher incidence of AD. The relative frequency of chromosome 21 and 13 aneuploidy was measured in nuclei derived from three brain regions (middle frontal gyrus, cerebellum and the inferior parietal lobule) from clinically defined AD individuals and age matched controls. Aneuploidy was found to be widespread throughout the brain with no consistent differences in the frequency aneuploidy between the tested regions in controls or AD cases. AD cases on average had a higher level of total somatic aneuploidy than control individuals. The majority of this difference was due to the twofold increase in frequency of trisomy 21 in AD cases relative to controls. The underlying hypothesis is therefore supported by this observation. Correlation analysis of total aneuploidy frequency and the subtypes suggest a mechanistic origin of monosomy is likely to be different for trisomy. Importantly the frequency of total aneuploidy is correlated with age in controls but only with the trisomy 21 subtype in AD cases. This implies that the mechanism controlling aneuploidy in controls is lost in AD. Finally, a method was developed that allowed the detection of allele specific nondisjunction using genotyping heterozygous SNPs across chromosome 21. This method showed the ability to detect mosaicism down to a 1% level. Using this technique, this project provided evidence for the lack of allele specificity of the nondisjunction events responsible for aneuploidy cells detected in the brain, suggesting a potential mechanism by which aneuploidy accumulates randomly throughout the brain over a lifetime.