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Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

2013; Springer Nature; Volume: 18; Issue: 11 Linguagem: Inglês

10.1038/mp.2013.1

1476-5578

Julien Chapuis, Franck Hansmannel, Marc Gistelinck, A Mounier, Caroline Van Cauwenberghe, Kristof Van Kolen, Frank Geller, Yoann Sottejeau, Denise Harold, Pierre Dourlen, Benjamin Grenier‐Boley, Yoichiro Kamatani, B. Delepine, Florie Demiautte, Diana Zélénika, Nadège Zommer, Malika Hamdane, Céline Bellenguez, Dartigues Jf, J J Hauw, Florent Letronne, A-M Ayral, Kristel Sleegers, Ann Schellens, Lies Vanden Broeck, Sebastiaan Engelborghs, Peter Paul De Deyn, Rik Vandenberghe, Michael O’Donovan, Michael J. Owen, Jacques Epelbaum, Marc Mercken, Eric Karran, Marcus Bantscheff, Gerard Drewes, Gérard Joberty, Dominique Campion, J-N Octave, Claudine Berr, Mark Lathrop, Patrick Callaerts, David M. A. Mann, Julie Williams, Luc Buée, Ilse Dewachter, Christine Van Broeckhoven, Philippe Amouyel, Dieder Moechars, Bart Dermaut, Jean‐Charles Lambert,

Machine Learning in Bioinformatics

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.