Chromosomal copy number variation in the normal human brain and Alzheimer's disease
Hyperploidy, i.e., neurons with a more than diploid DNA content, might be a significant source for neuronal complexity, intercellular diversity, and evolution. Genomic instability associated with hyperploidy, however, can also lead to developmental abnormalities and decreased cellular fitness. In the normal human brain, the number of hyperploid neurons, amounts to about 10%. In Alzheimer´s disease (AD), however, this number is more than doubled. Hyperploid neurons are increased already at preclinical stages of AD and are selectively affected by cell death during progression of the disease. These findings show that neuronal hyperploidy in AD is associated with a decreased viability. Hyperploidy of neurons, thus, represents a direct molecular signature of cells prone to death in AD. This adds hyperploidy to the list of critical molecular events that are shared between neurodegneration and malignant cell transformation. Irrespectively of whether hyperploidy results from a lack of aneuploidy clearance during brain development or an aberrant attempt of cell cycle reentry and DNA replication in the adult, it directs our attention to a failure of neuronal differentiation as the critical pathogenetic event and potential therapeutic target in neurodegeneration.
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