JNK3 Perpetuates Metabolic Stress Induced by Aβ Peptides

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2012 Sep 11

PMID 22958823

Citations 112

Authors

Sung Ok Yoon

Dong Ju Park

Jae Cheon Ryu

Hatice Gulcin Ozer

Chhavy Tep

Yong Jae Shin

Tae Hee Lim

Lucia Pastorino

Ajaya J Kunwar

James C Walton

Alan H Nagahara

Kun Ping Lu

Randy J Nelson

Mark H Tuszynski

Kun Huang

Affiliations

Soon will be listed here.

Abstract

Although Aβ peptides are causative agents in Alzheimer's disease (AD), the underlying mechanisms are still elusive. We report that Aβ42 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 Aβ42 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 Aβ42 production. Concomitantly, deletion of JNK3 from FAD mice results in a dramatic reduction in Aβ42 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.

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