Phosphorylation of p66Shc and forkhead proteins mediates Aβ toxicity

Excessive accumulation of amyloid beta-peptide (A beta) plays an early and critical role in synapse and neuronal loss in Alzheimer's Disease ( AD). Increased oxidative stress is one of the mechanisms whereby A beta induces neuronal death. Given the lessened susceptibility to oxidative stress exhibited by mice lacking p66Shc, we investigated the role of p66Shc in A beta toxicity. Treatment of cells and primary neuronal cultures with A beta caused apoptotic death and induced p66Shc phosphorylation at Ser36. Ectopic expression of a dominant-negative SEK1 mutant or chemical JNK inhibition reduced A beta-induced JNK activation and p66Shc phosphorylation ( Ser36), suggesting that JNK phosphorylates p66Shc. A beta induced the phosphorylation and hence inactivation of forkhead transcription factors in a p66Shc-dependent manner. Ectopic expression of p66ShcS36A or antioxidant treatment protected cells against A beta-induced death and reduced forkhead phosphorylation, suggesting that p66Shc phosphorylation critically influences the redox regulation of forkhead proteins and underlies A beta toxicity. These findings underscore the potential usefulness of JNK, p66Shc, and forkhead proteins as therapeutic targets for AD.