Cell cycle activation and aneuploid neurons in Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder, characterized by synaptic degeneration associated with fibrillar aggregates of the amyloid-ß peptide and the microtubule-associated protein tau. The progression of neurofibrillary degeneration throughout the brain during AD follows a predictive pattern which provides the basis for the neuropathological staging of the disease. This pattern of selective neuronal vulnerability against neurofibrillary degeneration matches the regional degree of neuronal plasticity and inversely recapitulates ontogenetic and phylogenetic brain development which links neurodegenerative cell death to neuroplasticity and brain development. Here, we summarize recent evidence for a loss of neuronal differentiation control as a critical pathogenetic event in AD, associated with a reactivation of the cell cycle and a partial or full replication of DNA giving rise to neurons with a content of DNA above the diploid level. Neurons with an aneuploid set of chromosomes are also present at a low frequency in the normal brain where they appear to be well tolerated. In AD, however, where the number of aneuploid neurons is highly increased, a rather selective cell death of neurons with this chromosomal aberrancy occurs. This finding add aneuploidy to the list of critical molecular events that are shared between neurodegeneration and oncogenesis. It defines a molecular signature for neuronal vulnerability and directs our attention to a failure of neuronal differentiation control as a critical pathogenetic event and potential therapeutic target in AD.