Alzheimer's Disease

Maladapted for Oxidative Stress

Science's STKE  10 May 2005:
Vol. 2005, Issue 283, pp. tw175
DOI: 10.1126/stke.2832005tw175

Alzheimer's disease is a neurodegenerative disease, and the accumulation of a toxic amyloid β peptide (Aβ) contributes to cell death. Smith et al. show that in cultured cell lines or primary cortical neurons, exposure to Aβ caused cell death and caused prolonged Ser36 phosphorylation of the adaptor protein p66Shc, which had been previously implicated in the cellular response to oxidative stress. Using PC12 cells overexpressing either wild-type p66Shc or a Ser36 to Ala mutant (p66ShcS36A), the authors showed that cells with the dominant-negative mutant were less susceptible to Aβ-induced apoptosis. Furthermore, overexpression of p66ShcS36A also reduced the abundance of reactive oxygen species (ROS) in cells exposed to Aβ compared with the amounts detected in cells overexpressing p66Shc or nontransfected cells. The SH-SY5Y neuroblastoma cell line was used to investigate the role of the c-Jun N-terminal kinase (JNK) pathway in Aβ-stimulated p66Shc phosphorylation and cell death. Overexpression of a dominant-negative SEK1 (the kinase upstream of JNK) or pharmacological inhibition of SEK1 protected cells from Aβ-induced cell death and inhibited phosphorylation of JNK and p66Shc. Finally, transcription factors of the Forkhead (FKH) family, which are known to stimulate the expression of genes encoding ROS scavenging enzymes, were phosphorylated in response to Aβ exposure in SH-SY5Y and primary cortical neuron cultures. Phosphorylation of these transcription factors results in their sequestration in the cytosol and inhibition of expression of their target genes. Overexpression of p66ShcS36A in PC12 cells inhibited phosphorylation of FKHR, which suggests a link between p66Shc and regulation of ROS scavenging enzymes through FKH. Thus, the authors suggest that Aβ mediates its toxicity through an increase in ROS that in turn activates the JNK pathway, which results in phosphorylation of p66Shc and FKH, which decreases the cell's capacity to detoxify ROS.

W. W. Smith, D. D. Norton, M. Gorospe, H. Jiang, S. Nemoto, N. J. Holbrook, T. Finkel, J. W. Kusiak, Phosphorylation of p66Shc and forkhead proteins mediates Aβ toxicity. J. Cell. Biol. 169, 331-339 (2005). [Abstract] [Full Text]