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  • Original Research Article
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Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease

Molecular Psychiatry volume 8, pages 413–422 (2003)Cite this article

A Corrigendum to this article was published on 31 October 2003

Abstract

Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a −499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the −499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

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Acknowledgements

This work was supported by grants from the Swiss National Science Foundation (32-62623.00 to GW, 31-56689.99 to JAH, 32-61623.00 to VM), the Juvenile Diabetes Research Foundation (1-2001-555 to GW), the Placide Nicod and the Octav and Marcella Botnar Foundations, the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés (701036), the Institut National de la Santé et de la Recherche Médicale (Réseau de Recherche en Santé Publique no. 494004), the CH et U de Lille and the Institut Pasteur de Lille. We thank all the Directors and Physicians of the retirement homes and Dr MT Hurtevent without whom this work would not have been possible. We thank Xavier Hermant and Sophie Machelart for skillful technical assistance.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale U508, Pasteur Institute, Lille, France

    N Helbecque, D Cottel & P Amouyel

  2. Department of Internal Medicine, CHUV-University Hospital, Lausanne, Switzerland

    A Abderrhamani, L Meylan, V Mooser, P Nicod, J-A Haefliger & G Waeber

  3. Institute of Cellular Biology and Morphology, CHUV-University Hospital, Lausanne, Switzerland

    A Abderrhamani, B Riederer & G Waeber

  4. Department of Pathology, CHUV-University Hospital, Lausanne, Switzerland

    J Miklossy

  5. Institute of Biology-CNRS 8090, Pasteur Institute, Lille, France

    J Delplanque, P Boutin & P Froguel

  6. Barts & The London Genome Centre, Queen Marys School of Medicine, London, UK

    P Froguel

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Correspondence to G Waeber.

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Helbecque, N., Abderrhamani, A., Meylan, L. et al. Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease. Mol Psychiatry 8, 413–422 (2003). https://doi.org/10.1038/sj.mp.4001344

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