Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

被引：282

作者：

Chapuis, J. ^{[1
,2
]}

Hansmannel, F. ^{[1
,2
]}

Gistelinck, M. ^{[3
]}

Mounier, A. ^{[1
,2
]}

Van Cauwenberghe, C. ^{[4
,5
]}

Kolen, K. V. ^{[6
]}

Geller, F. ^{[1
,2
]}

Sottejeau, Y. ^{[1
,2
]}

Harold, D. ^{[7
]}

Dourlen, P. ^{[1
,2
]}

Grenier-Boley, B. ^{[1
,2
]}

Kamatani, Y. ^{[8
]}

Delepine, B. ^{[9
]}

Demiautte, F. ^{[1
,2
]}

Zelenika, D. ^{[9
]}

Zommer, N. ^{[10
]}

Hamdane, M. ^{[10
]}

Bellenguez, C. ^{[1
,2
]}

Dartigues, J-F ^{[11
,12
,13
]}

Hauw, J-J ^{[14
]}

Letronne, F. ^{[1
,2
]}

Ayral, A-M ^{[1
,2
]}

Sleegers, K. ^{[4
,5
]}

Schellens, A. ^{[3
]}

Broeck, L. V. ^{[3
]}

Engelborghs, S. ^{[5
,15
,16
]}

De Deyn, P. P. ^{[5
,15
,16
]}

Vandenberghe, R. ^{[17
,18
]}

O'Donovan, M. ^{[7
]}

Owen, M. ^{[7
,19
]}

Epelbaum, J.

Mercken, M. ^{[6
]}

Karran, E. ^{[6
]}

Bantscheff, M. ^{[20
]}

Drewes, G. ^{[20
]}

Joberty, G. ^{[20
]}

Campion, D. ^{[21
,22
]}

Octave, J-N ^{[23
]}

Berr, C. ^{[24
]}

Lathrop, M. ^{[8
,9
]}

Callaerts, P. ^{[3
]}

Mann, D. ^{[25
]}

Williams, J. ^{[7
]}

Buee, L. ^{[10
]}

Dewachter, I. ^{[23
]}

Van Broeckhoven, C. ^{[4
,5
]}

Amouyel, P. ^{[1
,2
]}

Moechars, D. ^{[6
]}

Dermaut, B. ^{[1
,2
,3
]}

Lambert, J-C ^{[1
,2
]}

机构：

[1] Univ Lille Nord France, Inst Pasteur Lille, INSERM, U744, Lille, France

[2] Univ Lille Nord France, Inst Pasteur Lille, Lille, France

[3] VIB, Lab Behav & Dev Genet, Ctr Human Genet, Louvain, Belgium

[4] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

[5] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium

[6] Janssen Res Fdn, CNS Discovery, B-2340 Beerse, Belgium

[7] Cardiff Univ, Neurosci & Mental Hlth Res Inst,MRC,Ctr Neuropsyc, Dept Psychol Med & Neurol, Sch Med, Cardiff, S Glam, Wales

[8] Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France

[9] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France

[10] Univ Lille, Jean Pierre Aubert Res Ctr, INSERM, U837, Lille, France

[11] Univ Lille, INSERM, Jean Pierre Aubert Res Ctr, U897, Bordeaux, France

[12] Univ Victor Segalen, Bordeaux, France

[13] CHU Bordeaux, Ctr Memoire Ressources & Rech Bordeaux, Bordeaux, France

[14] Hop La Pitie Salpetriere, Lab Neuropathol Raymond Escourolle, AP HP, Paris, France

[15] Hosp Network Antwerp Middelheim & Hoge Beuken, Dept Neurol, Antwerp, Belgium

[16] Hosp Network Antwerp Middelheim & Hoge Beuken, Memory Clin, Antwerp, Belgium

[17] Univ Hosp Leuven Gasthuisberg, Dept Neurol, Louvain, Belgium

[18] Univ Leuven KULeuven, Louvain, Belgium

[19] INSERM, Psychiat & Neurosci Ctr, UMR 894, Paris, France

[20] Cellzome, Heidelberg, Germany

[21] Ctr Hosp Rouvray, INSERM, U614, Fac Med, Rouen, France

[22] Ctr Natl Reference Malad Alzheimer Sujet Jeune, Rouen, France

[23] Catholic Univ Louvain, FARL Inst Neurosci, B-1200 Brussels, Belgium

[24] Hop La Colombiere, INSERM, U888, Montpellier, France

[25] Univ Manchester, Dept Pathol Sci, Manchester, Lancs, England

来源：

MOLECULAR PSYCHIATRY | 2013年 / 18卷 / 11期

关键词：

Alzheimer; brain; BIN1; Drosophila; Tau; GENOME-WIDE ASSOCIATION; IDENTIFIES VARIANTS; COMMON VARIANTS; AMPHIPHYSIN-II; DISEASE; DROSOPHILA; BRAIN; PHOSPHORYLATION; ENDOCYTOSIS; MODEL;

D O I：

10.1038/mp.2013.1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 similar to 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 x 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.

引用

页码：1225 / 1234

页数：10

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