ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons

Down's syndrome ( DS) is characterized by mental retardation and development of Alzheimer's disease ( AD). Oxidative stress and mitochondrial dysfunction are both related to neurodegeneration in DS. Several genes in chromosome 21 have been linked to neuronal death, including the transcription factor ets- 2. Cortical cultures derived from normal and DS fetal brains were used to study the role of ets- 2 in DS neuronal degeneration. ets- 2 was expressed in normal human cortical neurons ( HCNs) and was markedly upregulated by oxidative stress. When overexpressed in normal HCNs, ets- 2 induced a stereotyped sequence of apoptotic changes leading to neuronal death. DS HCNs exhibit intracellular oxidative stress and increased apoptosis after the first week in culture ( Busciglio and Yankner, 1995). ets- 2 levels were increased in DS HCNs, and, between 7 and 14 d in vitro, DS HCNs showed increased bax, cytoplasmic translocation of cytochrome c and apoptosis inducing factor, and active caspases 3 and 7, consistent with activation of an apoptotic mitochondrial death pathway. Degeneration of DS neurons was reduced by dominant- negative ets- 2, suggesting that increased ets- 2 expression promotes DS neuronal apoptosis. In the human brain, ets- 2 expression was found in neurons and astrocytes. Strong ets- 2 immunoreactivity was observed in DS/ AD and sporadic AD brains associated with degenerative markers such as bax, intracellularAbeta, and hyperphosphorylated tau. Thus, in DS/ AD and sporadic AD brains, converging pathological mechanisms leading to chronic oxidative stress and ets-2 upregulation in susceptible neurons may result in increased vulnerability by promoting the activation of a mitochondrial- dependent proapoptotic pathway of cell death.