期刊
JOURNAL OF NEUROSCIENCE
卷 31, 期 47, 页码 16969-16976出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4491-11.2011
关键词
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资金
- Medical Research Council
- Alzheimer's Research United Kingdom
- Alzheimers Research UK [ART-PPG2009A-4] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/B/0224X] Funding Source: researchfish
- Medical Research Council [G0001285] Funding Source: researchfish
- MRC [G0001285] Funding Source: UKRI
Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-beta (A beta), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant A beta 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 A beta. 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 A beta 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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