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2011-11-23

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cc-by-nc-sa (c) Mazzitelli, Sonia et al., 2011
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/141737

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

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https://doi.org/10.1523/JNEUROSCI.4491-11.2011

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.

Subject

Antihormones, Amiloïdosi, Proteïnes quinases, Genètica, Ratolins (Animals de laboratori)

Subject (English)

Hormone antagonists, Amyloidosis, Protein kinases, Genetics, Mice (Laboratory animals)

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citation

MAZZITELLI, Sonia, et al. 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. Journal of Neuroscience. 2011. Vol. 31, num. 47, pags. 16969-16976. ISSN 0270-6474. [consulted: 15 of August of 2026]. Available at: https://hdl.handle.net/2445/141737

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