Alzpedia

Bridging integrator 1 (BIN1)

Synonyms: amphiphysin 2, AMPH2, AMPHL, SH3P9

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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.

References

Alzpedia Citations

  1. PICALM
  2. BACE1
  3. APP

External Citations

  1. AlzGene

Further Reading

Papers

  1. Tan MS, Yu JT, Tan L. Bridging integrator 1 (BIN1): form, function, and Alzheimer's disease. Trends Mol Med. 2013 Jul 17; PubMed.
  2. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM, . Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010 May 12;303(18):1832-40. PubMed.
  3. Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, Geller F, Sottejeau Y, Harold D, Dourlen P, Grenier-Boley B, Kamatani Y, Delepine B, Demiautte F, Zelenika D, Zommer N, Hamdane M, Bellenguez C, Dartigues JF, Hauw JJ, Letronne F, Ayral AM, Sleegers K, Schellens A, Broeck LV, Engelborghs S, De Deyn PP, Vandenberghe R, O'Donovan M, Owen M, Epelbaum J, Mercken M, Karran E, Bantscheff M, Drewes G, Joberty G, Campion D, Octave JN, Berr C, Lathrop M, Callaerts P, Mann D, Williams J, Buée L, Dewachter I, Van Broeckhoven C, Amouyel P, Moechars D, Dermaut B, Lambert JC, GERAD consortium. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013 Nov;18(11):1225-34. Epub 2013 Feb 12 PubMed.
  4. Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S, Van Eerdewegh P, Soares H, . Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer's disease. PLoS One. 2011;6(2):e16616. PubMed.
  5. Barral S, Bird T, Goate A, Farlow MR, Diaz-Arrastia R, Bennett DA, Graff-Radford N, Boeve BF, Sweet RA, Stern Y, Wilson RS, Foroud T, Ott J, Mayeux R, . Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory. Neurology. 2012 May 8;78(19):1464-71. PubMed.
  6. Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R, . Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet. 2011 Feb;7(2):e1001308. PubMed.
  7. Kauwe JS, Cruchaga C, Karch CM, Sadler B, Lee M, Mayo K, Latu W, Su'a M, Fagan AM, Holtzman DM, Morris JC, , Goate AM. Fine mapping of genetic variants in BIN1, CLU, CR1 and PICALM for association with cerebrospinal fluid biomarkers for Alzheimer's disease. PLoS One. 2011;6(2):e15918. PubMed.
  8. Liu G, Zhang S, Cai Z, Li Y, Cui L, Ma G, Jiang Y, Zhang L, Feng R, Liao M, Chen Z, Zhao B, Li K. BIN1 gene rs744373 polymorphism contributes to Alzheimer's disease in East Asian population. Neurosci Lett. 2013 Jun 7;544:47-51. PubMed.