Induction of GADD34 Regulates the Neurotoxicity of Amyloid β

The possible roles played by growth arrest and DNA damage-inducible gene 34 (GADD34) in Alzheimer's disease (AD) are so far less understood. In this study, we found that GADD34 was increased in the brains of AD transgenic J20 mice. The deposition of β-amyloid (Aβ) peptide is the main component of neurotic plaques in AD brain. Thus, we examined the effect of Aβ in the expression of GADD34 in human SH-SY5Y cells in vitro. Amyloid β (Aβ1-42) treatment led to increased expression of GADD34. Pretreatment with 50 nmol/L of c-Jun N-terminal kinases (JNK) inhibitor SP600125 abolished the upregulation of GADD34. c-Jun silencing by transfection with c-Jun small-interfering RNA abolished the effects of Aβ1-42 on the expression of GADD34. Importantly, chromatin immunoprecipitation studies verified the ability of c-Jun to bind to the GADD34 promoter, and this ability was increased more than 3-fold by Aβ1-42. These data suggest that the induction of GADD34 by Aβ is mediated by JNK/c-Jun pathway. Finally, depletion of GADD34 significantly rescued Aβ-induced cell apoptosis as evidenced by a marked decrease in the number of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells. Consistently, knockdown of GADD34 attenuated caspase 3 activation induced by Aβ1-42.