P3‐054: Requirement of active JNK for beta‐amyloid deposition

The progressive accumulation of amyloid b (Ab) in the brain following the sequential cleavage of the amyloid precursor protein (APP) is one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). However, the molecular mechanism of Ab neurotoxicity in vivo is not completely understood. In vitro, Ab promotes neuronal apoptosis via the c-Jun NH2-terminal protein kinase (JNK), a mitogen-activated protein kinase (MAPK) whose activity is increased upon phosphorylation by MAPK kinases (MKK4 and MKK7). To determine the requirement of JNK signaling in the development of AD, we have tested the effect of the loss of JNK activity in the brain of mutant mice that develop the pathology, including Ab deposition, as soon as 4-6 months of age. Our results demonstrate that the absence of MKK4 and MKK7 expression prevents the formation of senile plaques. Decreased APP phosphorylation at threonine 668 associated with the loss of MKK4 and MKK7 constitutes one mechanism by which JNK signaling contributes to increasing Ab production. Together, our results provide for the first time strong genetic evidence that inhibition of JNK activity constitutes a potential novel strategy for the treatment of AD.