Genomic Mosaicism Increases APP Genes in Alzheimer’s disease

A new study entitled “Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer’s disease brains” identified genomic changes in single neurons as an underlying mechanism in sporadic Alzheimer’s disease. The study was published in the journal eLife.

Alzheimer’s disease (AD) is a common form of dementia and it occurs within familial lineages due to mutations in the APP gene (short for amyloid precursor protein). This gene encodes β-amyloid (Aβ) protein that accumulates to form β-amyloid plaques — one of the hallmarks of AD — leading to a stronger presentation of the APP gene, which increases AD pathogenesis. However, familial AD accounts only for less than 5% of all AD cases. Notably, the link between APP and familial AD is not observed in sporadic AD cases, which were shown to lack APP amplification.

A research team at the Dorris Neuroscience Center, The Scripps Research Institute hypothesized that a phenomenon known as genomic mosaicism might be the underlying cause for sporadic brain diseases — in this case, for sporadic AD. Classically, the genome is normally passed from cell to cell and expected to exist in the same way in every cell of an individual. However, neurons in normal brains were shown to exhibit somatic variability, i.e., genomic mosaicisms where two or more populations of cells have different genomes. However, the functional significance of this neuron genomic mosaicism remains unknown. Here the team of researchers hypothesized that DNA content variation (DCV), one of the ways genomic mosaiscism can arise, can indeed alter the expression of APP copy number in single neurons, leading to sporadic AD.

The team performed experiments in the laboratory and discovered in single neurons of sporadic AD brains increased DNA amounts, together with more copy numbers of the APP. Specifically, the nuclei of some neurons in sporadic AD brains exhibited higher variability, with an almost 8% increase in their DNA content when compared to healthy controls. Additionally, in single neurons, the team discovered amplifications of the APP gene locus in the range of 12 copies in single neurons.

This study identified DNA content variation in single neurons leading to the increased expression of the APP gene in sporadic AD, suggesting genomic mosaicism as a driving force in diseases of the central nervous system.