1. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology
- Author
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Diana Zelenika, Luc Buée, C. Van Broeckhoven, Franck Hansmannel, A-M Ayral, Kristof Van Kolen, C. Van Cauwenberghe, P.P. De Deyn, Marcus Bantscheff, Y Kamatani, Julie Williams, Rik Vandenberghe, Claudine Berr, Dominique Campion, Benjamin Grenier-Boley, N Zommer, Jacques Epelbaum, Michael John Owen, M Hamdane, Diederik Moechars, Céline Bellenguez, J-J Hauw, Denise Harold, J-N Octave, Patrick Callaerts, Julien Chapuis, J. F. Dartigues, Yoann Sottejeau, David M. A. Mann, Michael Conlon O'Donovan, Ilse Dewachter, Pierre Dourlen, Gerard Joberty, Anais Mounier, Florie Demiautte, Sebastiaan Engelborghs, Marc Gistelinck, J-C Lambert, Florent Letronne, Eric Karran, A Schellens, Lies Vanden Broeck, Bart Dermaut, Kristel Sleegers, M Mercken, Philippe Amouyel, B Delepine, Mark Lathrop, F Geller, Gerard Drewes, Faculty of Psychology and Educational Sciences, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and GERAD Consortium
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Apolipoprotein E ,Mathematics(all) ,BIN1 ,Gene Expression ,Genome-wide association study ,Plaque, Amyloid ,Mice ,0302 clinical medicine ,Gene expression ,Drosophila Proteins ,ALZHEIMER ,Cells, Cultured ,Medicine(all) ,0303 health sciences ,Nuclear Proteins ,Human brain ,3. Good health ,Psychiatry and Mental health ,Chemistry ,medicine.anatomical_structure ,Drosophila melanogaster ,Original Article ,Drosophila ,Alzheimer's disease ,Endophenotypes ,brain ,tau Proteins ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Alzheimer Disease ,Genetic predisposition ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Allele ,Molecular Biology ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Tumor Suppressor Proteins ,Neurotoxicity ,medicine.disease ,Molecular biology ,Case-Control Studies ,Nerve Degeneration ,Alzheimer ,Human medicine ,Tau ,Carrier Proteins ,030217 neurology & neurosurgery ,Synaptosomes ,Transcription Factors - Abstract
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology. ispartof: Molecular Psychiatry vol:18 issue:11 pages:1225-1234 ispartof: location:England status: published
- Published
- 2013
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