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Springer Nature [academic journals on nature.com], Molecular Psychiatry, 11(18), p. 1225-1234, 2013

DOI: 10.1038/mp.2013.1

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

Journal article published in 2013 by J; JFA; CORA; Hansmannel F; Gistelinck Marc; U0070364; 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 Jul Chapuis, Franck Hansmannel, Marc Gistelinck, Anais Mounier, C. Van Cauwenberghe, K. V. Kolen, F. Geller, Y. Sottejeau, Denise Harold, P. Dourlen, B. Grenier-Boley, Y. Kamatani, B. Delepine, F. Demiautte, D. Zelenika and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.Molecular Psychiatry advance online publication, 12 February 2013; doi:10.1038/mp.2013.1.