JNK regulates APP cleavage and degradation in a model of Alzheimer's disease

Abstract

Secretion of Amyloid-beta peptide (Aβ) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD).We show that phosphorylation of APP on threonine 668 may play a role in APP metabolism in H4-APPsw cell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degradation and prevented APP phosphorylation at T668. This results in a significant drop of βAPPs, Aβ fragments and Aβ circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metabolism, since the peptide reduced the rate of the amyloidogenic processing in favour of the non-amyloidogenic one. All together our results suggest an important link between APP metabolism and the JNK pathway and contribute to shed light on the molecular signalling pathway of this disease indicating JNK as an innovative target for AD therapy.

Keywords

• Alzheimer's disease
• c-Jun N-terminal kinase
• Amyloid-precursor protein
• Oligomers
• Phosphorylation
• D-JNKI1