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.
Publication types
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Meta-Analysis
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / biosynthesis
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Adaptor Proteins, Signal Transducing / genetics*
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology*
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Animals
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Brain / metabolism
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Brain / pathology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Case-Control Studies
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Cells, Cultured
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Drosophila Proteins / deficiency
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism
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Endophenotypes
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Gene Expression / genetics
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Genetic Predisposition to Disease / genetics*
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Humans
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Mice
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Nerve Degeneration / genetics
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Nerve Degeneration / pathology
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics*
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Plaque, Amyloid / pathology
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Polymorphism, Single Nucleotide / genetics
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Synaptosomes / pathology
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics*
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tau Proteins / antagonists & inhibitors
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tau Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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BIN1 protein, human
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Carrier Proteins
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Drosophila Proteins
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MAPT protein, human
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Nuclear Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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bicoid interacting protein 1, Drosophila
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tau Proteins