Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
Mol Psychiatry
; 18(11): 1225-34, 2013 Nov.
Article
in En
| MEDLINE
| ID: mdl-23399914
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 â¼28 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Nuclear Proteins
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Tau Proteins
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Genetic Predisposition to Disease
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Tumor Suppressor Proteins
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Adaptor Proteins, Signal Transducing
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Alzheimer Disease
Type of study:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
/
Systematic_reviews
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Psychiatry
Journal subject:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Year:
2013
Document type:
Article
Affiliation country: