Mechanisms of neuronal death in Down's syndrome

There is growing evidence that neuronal death in Down's syndrome is due to apoptotic mechanisms. The phenomena, however, that trigger and regulate programmed cell death in the Down's syndrome-related neurodegeneration are still much debated. In vitro evidence has suggested that the main factor responsible for neuronal death in this condition is the accumulation of beta-amyloid, due to the overexpression of its precursor protein. Another hypothesis argues for the importance of reactive oxygen species in neuronal death. However, the in vivo findings do not entirely support either theories. We propose that neuronal apoptosis, as well as the formation of Alzheimer-type pathology, in Down's syndrome is due to an aberrant re-entry of neurones into the cell division cycle. Due to the simultaneous overexpression of conflicting cell cycle regulatory signals the mitogenic amyloid precursor and the differentiation factor S100, the cell cycle is abandoned. Subsequently the cell cycle arrest may lead to either the formation of Alzheimer-related pathology or to apoptotic cell death.