Sci. Signal., 11 September 2012
Neuroscience JNKing Neurons
Science Signaling, AAAS, Washington, DC 20005, USA
In Alzheimers disease, processing of the transmembrane amyloid precursor protein (APP) generates soluble β-amyloid (Aβ) peptides, such as Aβ42, that oligomerize, aggregate, and form plaques in the brain, resulting in neurodegeneration. Yoon et al. investigated the role of c-Jun N-terminal kinase (JNK) activation by the endoplasmic reticulum (ER) stress response, which is activated in brain from patients who died of Alzheimers disease. Blocking protein translation triggers ER stress and can be induced by activation of the kinase AMPK, which inhibits mTOR signaling by phosphorylating TSC2 at Ser3187 to activate TSC2 and by phosphorylating Raptor at Ser792 to inhibit Raptor. Treatment of cultured rat hippocampal neurons with Aβ42 induced a translational block and was associated with increased activation of AMPK (as indicated by phosphorylation of Thr172) and increased phosphorylation of Ser3187 in TSC2 and of Ser792 in Raptor. JNK3 phosphorylated Thr668 in APP in vitro. The authors hypothesized that this phosphorylation event would promote amyloidogenic processing of cell surface APP by triggering its endocytosis. Activation of JNK with anisomycin initially increased, then decreased, the amount of cell surface APP, an effect that required phosphorylation of Thr668 and was inhibited by the concurrent application of peptides derived from JNK-interacting protein (JIP) to inhibit JNK. Furthermore, anisomycin treatment increased the processing of APP, which required phosphorylation of Thr668. Kinase assays indicated that JNK3 activity was higher in Alzheimers disease patients than in normal cases and in FAD mice, which are a model for Alzheimers disease, than in control mice. Immunohistochemistry with a pan-JNK antibody detected phosphorylated and activated JNK near plaques in FAD mice with JNK3 (FAD:JNK3+/+) but not in FAD mice lacking JNK3 (FAD:JNK3–/–), indicating that JNK3 is the primary JNK isoform that is activated in FAD mice. Deletion of JNK3 in FAD mice resulted in decreased Aβ42 abundance, diminished phosphorylation of Thr668 in APP, reductions in the number and size of plaques, and improved cognition (as indicated by increased long-term retention of fear memories) compared with FAD:JNK3+/+ mice. Phosphorylation of the ribosomal protein S6 at Ser235 and Ser236, a marker for active translation, was increased in FAD:JNK3–/– mice; whereas phosphorylation of Raptor at Ser792 was increased in FAD:JNK3+/+ mice, suggesting a block in global translation in FAD:JNK3+/+ mice. Western blot analysis indicated increased ER stress in FAD:JNK3+/+ compared with FAD:JNK3–/– mice and in cortical samples from Alzheimers disease patients compared with control cases. Thus, targeting JNK3 in Alzheimers disease could reduce the processing of APP into oligomeric Aβ peptides and the ER stress caused by Aβ peptides.
S. O. Yoon, D. J. Park, J. C. Ryu, H. G. Ozer, C. Tep, Y. J. Shin, T. H. Lim, L. Pastorino, A. J. Kunwar, J. C. Walton, A. H. Nagahara, K. P. Lu, R. J. Nelson, M. H. Tuszynski, K. Huang, JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron 75, 824–837 (2012). [Online Journal]
Citation: W. Wong, JNKing Neurons. Sci. Signal. 5, ec237 (2012).
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