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

Chapuis, J, Hansmannel, F, Gistelinck, M, Mounier, A, Van Cauwenberghe, C, Kolen, K V, Geller, F, Sottejeau, Y, Harold, D, Dourlen, P, Grenier-Boley, B, Kamatani, Y, Delepine, B, Demiautte, F, Zelenika, D, Zommer, N, Hamdane, M, Bellenguez, C, Dartigues, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, Sleegers, K, Schellens, A, Broeck, L V, Engelborghs, S, De Deyn, P P, Vandenberghe, R, O'Donovan, Michael Conlon, Owen, Michael John, Epelbaum, J, Mercken, M, Karran, E, Bantscheff, M, Drewes, G, Joberty, G, Campion, D, Octave, J-N, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, Julie, Buée, L, Dewachter, I, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B and Lambert, J-C 2013. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology [Article]. Molecular Psychiatry 18 (11) , pp. 1225-1234. 10.1038/mp.2013.1

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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.

Item Type: Article
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
ISSN: 1359-4184
Last Modified: 10 Jan 2018 06:37
URI: http://orca.cf.ac.uk/id/eprint/75860

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