Somatic Mosaicism and Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, currently with no effective preventative treatment. It is poised to become one of the greatest healthcare challenges and is already amongst the costliest in the Western world. Autosomal-dominant mutations have been identified several genes in cases of early-onset familial AD. However the majority of cases (>95%) are defined as late-onset sporadic AD with poorly definedgenetic association. The most supported model of AD pathogenesis is the Amyloid Cascade Hypothesis, which posits an increase in the production of the toxic amyloid-beta peptide as the central event in AD pathology. The amyloid precursor protein (APP, chromosome 21), cleaved to form amyloid-beta, carries rare familial mutations, as do two proteins (PSEN1 and PSEN2) involved in APP processing. Down’s syndrome (Trisomy 21) has been long associated with a significantly higher risk of AD.This heightened risk is presumably due to the duplication of the APP locus on chromosome 21. Germlineosaicism of trisomy 21 has been observed inearly onset AD, and several limited studies have observed increased somatic mosaicism of trimsomy 21 in late-onset AD. This project aimed to establish robust measurementsof the frequency of trisomy 21 mosaicism inlate-onset AD and age-matched control brain cells. The protocol utilised FISH probes for chromosome 21, and 13 (as a standard), to quantify aneuploidyof these two chromosomes. Results from FISH showed a significant increase of aneuploidy in both chromosomes 13 and 21 in AD patients over controls. The increase in aneuploidy was due to trisomy, with monosomy showing no difference. The trisomy levels exhibited by both chromosomes were intimately linked within individuals, indicating a cellular bias or underlying mechanism affecting both chromosomes. The results found here establish a firm foundation for aneuploidy, specifically trisomy,in AD, and pave the way for further investigation into this phenomenon. Key words:Alzheimer's disease,Down Syndrome, Amyloid Cascade Hypothesis, Somatic mosaicism, Aneuploidy.