Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline

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J Psychiatry Neurosci 2015;40(3):151-161

Sarah Gourmaud, MS; Claire Paquet, MD, PhD; Julien Dumurgier, MD, PhD; Clarisse Pace, MS; Constantin Bouras, MD, PhD; Françoise Gray, MD, PhD; Jean-Louis Laplanche, PharmD, PhD; Eliane F. Meurs, PhD; François Mouton-Liger, PhD*; Jacques Hugon, MD, PhD*


Background: Alzheimer disease is characterized by cognitive decline, senile plaques of β-amyloid (Aβ) peptides, neurofibrillary tangles composed of hyperphosphorylated τ proteins and neuronal loss. Aβ and τ are useful markers in the cerebrospinal fluid (CSF). C-Jun N-terminal kinases (JNKs) are serine-threonine protein kinases activated by phosphorylation and involved in neuronal death.

Methods: In this study, Western blots, enzyme-linked immunosorbent assay and histological approaches were used to assess the concentrations of Aβ, τ and JNK isoforms in postmortem brain tissue samples (10 Alzheimer disease and 10 control) and in CSF samples from 30 living patients with Alzheimer disease and 27 controls with neurologic disease excluding Alzheimer disease. Patients with Alzheimer disease were followed for 1–3 years and assessed using Mini–Mental State Examination scores.

Results: The biochemical and morphological results showed a significant increase of JNK3 and phosphorylated JNK levels in patients with Alzheimer disease, and JNK3 levels correlated with Aβ42 levels. Confocal microscopy revealed that JNK3 was associated with Aβ in senile plaques. The JNK3 levels in the CSF were significantly elevated in patients with Alzheimer disease and correlated statistically with the rate of cognitive decline in a mixed linear model.

Limitations: The study involved different samples grouped into 3 small cohorts. Evaluation of JNK3 in CSF was possible only with immunoblot analysis.

Conclusion: We found that JNK3 levels are increased in brain tissue and CSF from patients with Alzheimer disease. The finding that increased JNK3 levels in CSF could reflect the rate of cognitive decline is new and merits further investigation.

*These authors contributed equally to this work.

Submitted Feb. 24, 2014; Revised June 26, Aug. 12, 2014; Accepted Aug. 19, 2014; Early-released Dec. 2, 2014

Acknowledgements: The authors thank members of the INSERM Units 839 and 942 and members of the Research Memory Center Paris North for their contributions to the study.

Affiliations: Institut du Fer à Moulin, Inserm UMR-S 839 and UMR-S 942, Lariboisière Hospital, Paris, France (S. Gourmaud, C. Paquet, J. Dumurgier, C. Pace, F. Mouton-Liger, J. Hugon); Research Memory Centre, Paris Nord Ile de France, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris Diderot, France (C. Paquet, J. Dumurgier, J. Hugon); Department of Histology (S. Gourmaud, C. Paquet, J. Dumurgier, F. Mouton-Liger, J. Hugon), Department of Pathology (F. Gray) and Department of Biochemistry (J.-L. Laplanche), Saint-Louis, Lariboisière, Fernand- Widal Hospital, AP-HP, University of Paris, Diderot, France; Department of Neuropsychiatry, Geneva University Hospital, Geneva, Switzerland (C. Bouras); Institut Pasteur, Hepacivirus and Innate Immunity Unit, Paris, France (E. Meurs).

Competing interests: C. Paquet declares a grant from Fondation Phillippe Chatrier and has been paid for travel expenses by Novartis. J. Dumurgier declares grants from Institut Servier and Phillips Foundataion and has been paid for travel expenses by Novartis. J. Hugon is a consultant for Xigen, Roche and Sanofi Laboratories. No other competing interests were declared.

Contributors: C. Bouras, F. Gray, J.-L. Laplanche, E. Meurs, F. Mouton-Liger and J. Hugon designed the study. S. Gourmaud, C. Paquet and J. Dumurgier acquired and analyzed the data. C. Pace also acquired the data, and F. Mouton-Liger and J. Hugon also analyzed the data. S. Gourmaud and J. Hugon wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.140062

Correspondence to: J. Hugon, Memory Clinical Centre Paris Nord Ile-de-France, 200 rue du Faubourg Saint-Denis, 75010 Paris, France;