Induction of GADD34 Regulates the Neurotoxicity of Amyloid {beta}

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.
Source: American Journal of Alzheimer's Disease and Other Dementias - Category: Geriatrics Authors: Tags: Current Topics in Research Source Type: research