Sarah Gourmaud1, Claire Paquet2, Julien Dumurgier2, Clarisse Pace3, Constantin Bouras4, Françoise Gray5, Jean-Louis Laplanche6, Eliane F Meurs7, François Mouton-Liger8, Jacques Hugon9. 1. Institut du Fer à Moulin, Inserm UMR-S 839 and UMR-S 942, Lariboisière Hospital, the Department of Histology, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, Paris, France. 2. Institut du Fer à Moulin, Inserm UMR-S 839 and UMR-S 942, the Research Memory Centre, Paris Nord Ile de France, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, and the Department of Histology, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, France. 3. Institut du Fer à Moulin, Inserm UMR-S 839 and UMR-S 942, Lariboisière Hospital, Paris, France. 4. Department of Neuropsychiatry, Geneva University Hospital, Geneva, Switzerland. 5. Department of Pathology, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, France. 6. Department of Biochemistry, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, France. 7. Institut Pasteur, Hepacivirus and Innate Immunity Unit, Paris, France. 8. Institut du Fer à Moulin, Inserm UMR-S 839 and UMR-S 942, Lariboisière Hospital, and the Department of Histology, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, France. 9. Institut du Fer à Moulin, Inserm UMR-S 839 and UMR-S 942, Lariboisière Hospital, the Research Memory Centre, Paris Nord Ile de France, and the Department of Histology, Saint-Louis, Lariboisière, Fernand-Widal Hospital, AP-HP, University of Paris, Diderot, France.
Abstract
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.
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.
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