Amyloid-beta-42 (A beta 42) has been implicated in the pathogenesis of Alzheimer's disease (AD). Neuronal A beta 42 expression induces apoptosis and decreases survival and locomotive activity in Drosophila. However, the mechanism by which A beta 42 induces these neuronal impairments is unclear. In this study, we investigated the underlying pathway in theses impairments. JNK activity was increased in A beta 42-expressing brains, and the A beta 42-induced defects were rescued by reducing JNK or caspase activity through genetic modification or pharmacological treatment. In addition, these impairments were restored by Drosophila forkhead box subgroup O (dFOXO) deficiency. These results suggest that the JNK/dFOXO pathway confers a therapeutic potential for AD. (C) 2012 Elsevier Inc. All rights reserved.