JNK3 perpetuates metabolic stress induced by A? peptides.

ABSTRACT: Although A? peptides are causative agents in Alzheimer's disease (AD), the underlying mechanisms are still elusive. We report that A?42 induces a translational block by activating AMPK, thereby inhibiting the mTOR pathway. This translational block leads to widespread ER stress, which activates JNK3. JNK3 in turn phosphorylates APP at T668, thereby facilitating its endocytosis and subsequent processing. In support, pharmacologically blocking translation results in a significant increase in A?42 in a JNK3-dependent manner. Thus, JNK3 activation, which is increased in human AD cases and a familial AD (FAD) mouse model, is integral to perpetuating A?42 production. Concomitantly, deletion of JNK3 from FAD mice results in a dramatic reduction in A?42 levels and overall plaque loads and increased neuronal number and improved cognition. This reveals AD as a metabolic disease that is under tight control by JNK3.

SUBMITTER: Yoon SO 

PROVIDER: S-EPMC3438522 | biostudies-other | 2012 Sep

REPOSITORIES: biostudies-other