Program in Molecular Medicine
Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Transgenic; Neurons; Plaque, Amyloid
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-beta (Abeta), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant Abeta production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to Abeta. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in Abeta production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for gamma-mediated cleavage of the C-terminal fragment of APP produced by beta-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD.
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DOI of Published Version
J Neurosci. 2011 Nov 23;31(47):16969-76. doi: 10.1523/JNEUROSCI.4491-11.2011. Link to article on publisher's site
The Journal of neuroscience : the official journal of the Society for Neuroscience
Mazzitelli, Sonia; Xu, Ping; Ferrer, Isidre; Davis, Roger J.; and Tournier, Cathy, "The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo" (2011). Davis Lab Publications. 40.
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