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

Autor: 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
Přispěvatelé: Faculty of Psychology and Educational Sciences, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, GERAD Consortium
Jazyk: angličtina
Rok vydání: 2013
Předmět:
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
Zdroj: Molecular Psychiatry
Molecular psychiatry
ISSN: 1359-4184
DOI: 10.1038/mp.2013.1
Popis: 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
Databáze: OpenAIRE
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