title: 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.
abstract: Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-β (Aβ), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant Aβ 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 Aβ. 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 Aβ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for γ-mediated cleavage of the C-terminal fragment of APP produced by β-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.
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
authors: Sonia
authors: S
authors: Mazzitelli
authors: Ping
authors: P
authors: Xu
authors: Isidre
authors: I
authors: Ferrer
authors: Roger J
authors: RJ
authors: Davis
authors: Cathy
authors: C
authors: Tournier
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
chemical_list: D016564:Amyloid beta-Protein Precursor; D048031:JNK Mitogen-Activated Protein Kinases