Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology
Top Cited Papers
Open Access
- 12 February 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Psychiatry
- Vol. 18 (11), 1225-1234
- https://doi.org/10.1038/mp.2013.1
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.Keywords
This publication has 24 references indexed in Scilit:
- Defective Membrane Remodeling in Neuromuscular Diseases: Insights from Animal ModelsPLoS Genetics, 2012
- Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's diseaseMolecular Psychiatry, 2012
- Identification of common variants influencing risk of the tauopathy progressive supranuclear palsyNature Genetics, 2011
- Genome-wide Analysis of Genetic Loci Associated With Alzheimer DiseaseJAMA, 2010
- Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic AssociationsPLoS Genetics, 2010
- Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusionsNature Genetics, 2010
- Differential Effects of Tau on the Integrity and Function of Neurons Essential for Learning in DrosophilaJournal of Neuroscience, 2010
- Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's diseaseNature Genetics, 2009
- The membrane-tubulating potential of amphiphysin 2/BIN1 is dependent on the microtubule-binding cytoplasmic linker protein 170 (CLIP-170)European Journal of Cell Biology, 2009
- Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's diseaseMolecular Psychiatry, 2009