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

Sonia Mazzitelli, Ping Xu, Isidre Ferrer, Roger J. Davis, Cathy Tournier

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 thatJNKsignaling 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.

Original languageEnglish
Pages (from-to)16969-16976
Number of pages8
JournalJournal of Neuroscience
Volume31
Issue number47
DOIs
Publication statusPublished - Nov 23 2011

Fingerprint

JNK Mitogen-Activated Protein Kinases
Amyloid beta-Protein Precursor
Amyloid Plaques
Alzheimer Disease
Proteins
Phosphorylation
Neurons
Amyloid Precursor Protein Secretases
Threonine
Amyloid
Signal Transduction
Brain
Genes
protein kinase N

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Mazzitelli, Sonia; Xu, Ping; Ferrer, Isidre; Davis, Roger J.; Tournier, Cathy.

In: Journal of Neuroscience, Vol. 31, No. 47, 23.11.2011, p. 16969-16976.

Research output: Contribution to journalArticle

Mazzitelli, Sonia ; Xu, Ping ; Ferrer, Isidre ; Davis, Roger J. ; 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. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 47. pp. 16969-16976.
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