Bridging integrator 1 (BIN1) is a widely expressed adaptor protein that is part of the Bin1/amphiphysin/RVS167 (BAR) family. BIN1 functions in clathrin-mediated endocytosis and endocytic recycling, as does the AD risk gene PICALM. Whereas brain-specific isoforms may be involved in the retrieval of synaptic vesicles, ubiquitous isoforms of BIN1 participate in apoptosis, inflammation and calcium homeostasis.
The bulk of the scientific literature on BIN1 concerns its initially identified roles in tumor suppression and muscle development, but in 2010, a large genome-wide association study (GWAS) discovered that BIN1 was a risk factor for late-onset Alzheimer’s disease. This association was confirmed in subsequent GWAS in different populations and in meta-analyses, and BIN1 remains near the top of AlzGene.
The pathogenic mechanism of BIN1 is unknown. A clustering of high-risk polymorphisms upstream of the gene points toward a potential effect on transcription, and AD patients carrying such BIN1 variants have been found to have elevated BIN1 expression in the brain. DNA methylation of the BIN1 promoter has been suggested as a possible epigenetic mechanism influencing AD risk.
BIN1 has also been proposed to modulate tau pathology, but the AD-associated variants known to date do not affect CSF tau levels. As an endocytic accessory protein, BIN1 could potentially affect BACE trafficking and APP metabolism, as well. The BIN1 risk locus has been reported to track with certain brain imaging features of AD.
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