Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.
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DOI：
10.1038/mp.2013.1
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发表时间：
2013-11
影响因子：
11
通讯作者：
Lambert, J-C
中科院分区：
文献类型：
--
作者：
Chapuis, J.;Hansmannel, F.;Gistelinck, M.;Mounier, A.;Van Cauwenberghe, C.;Kolen, K. V.;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, J-F;Hauw, J-J;Letronne, F.;Ayral, A-M;Sleegers, K.;Schellens, A.;Broeck, L. V.;Engelborghs, S.;De Deyn, P. P.;Vandenberghe, R.;O'Donovan, M.;Owen, M.;Epelbaum, J.;Mercken, M.;Karran, E.;Bantscheff, M.;Drewes, G.;Joberty, G.;Campion, D.;Octave, J-N;Berr, C.;Lathrop, M.;Callaerts, P.;Mann, D.;Williams, J.;Buee, L.;Dewachter, I.;Van Broeckhoven, C.;Amouyel, P.;Moechars, D.;Dermaut, B.;Lambert, J-C
全基因组关联研究（GWAS）已经确定BIN 1基因上游区域是继APOE之后阿尔茨海默病（AD）中最重要的遗传易感性位点。我们报告说，BIN 1转录水平在AD大脑中增加，并确定了一种新的3 bp插入等位基因，位于BIN 1上游28 kb处，它增加了（i）体外转录活性，（ii）人脑中BIN 1表达水平和（iii）三个独立病例对照队列中的AD风险（荟萃分析比值比为1.20（1.14-1.26）（P=3.8 × 10−11））。有趣的是，在三种不同的测定中，果蝇BIN 1直系同源物Amph的表达减少抑制了Tau介导的神经毒性。因此，Tau和BIN 1在人神经母细胞瘤细胞和小鼠脑中共定位并相互作用。最后，3bp插入与AD脑中的Tau而不是淀粉样蛋白负荷相关。我们提出BIN 1通过调节Tau病理学介导AD风险。
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.
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影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
11
作者：
通讯作者：
--
影响因子：
4.5
作者：
Cowling BS;Toussaint A;Muller J;Laporte J
通讯作者：
Laporte J
影响因子：
6.6
作者：
Meunier, Brigitte;Quaranta, Muriel;Leprince, Corinne
通讯作者：
Leprince, Corinne
影响因子：
5.3
作者：
Kosmidis, Stylianos;Grammenoudi, Sofia;Skoulakis, Efthimios M. C.
通讯作者：
Skoulakis, Efthimios M. C.