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

J Chapuis; F Hansmannel; M Gistelinck; A Mounier; C Van Cauwenberghe; K V Kolen; F Geller; Y Sottejeau; D Harold; P Dourlen; B Grenier-Boley; Y Kamatani; B Delepine; F Demiautte; D Zelenika; N Zommer; M Hamdane; C Bellenguez; J-F Dartigues; J-J Hauw; F Letronne; A-M Ayral; K Sleegers; A Schellens; L V Broeck; S Engelborghs; P P De Deyn; R Vandenberghe; M O'Donovan; M Owen; J Epelbaum; M Mercken; E Karran; M Bantscheff; G Drewes; G Joberty; D Campion; J-N Octave; C Berr; M Lathrop; P Callaerts; D Mann; J Williams; L Buée; I Dewachter; C Van Broeckhoven; P Amouyel; D Moechars; B Dermaut; J-C Lambert

doi:10.1038/mp.2013.1

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

J Chapuis, F Hansmannel, M Gistelinck, A Mounier, C Van Cauwenberghe, K V Kolen, F Geller, Y Sottejeau, D Harold, P Dourlen, B Grenier-Boley, Y Kamatani, B Delepine, F Demiautte, D Zelenika, N Zommer, M Hamdane, C Bellenguez, J-F Dartigues, J-J HauwF Letronne, A-M Ayral, K Sleegers, A Schellens, L V Broeck, S Engelborghs, P P De Deyn, R Vandenberghe, M O'Donovan, M Owen, J Epelbaum, M Mercken, E Karran, M Bantscheff, G Drewes, G Joberty, D Campion, J-N Octave, C Berr, M Lathrop, P Callaerts, D Mann, J Williams, L Buée, I Dewachter, C Van Broeckhoven, P Amouyel, D Moechars, B Dermaut, J-C Lambert

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Molecular psychiatry
Volume	18
Issue number	11
DOIs	https://doi.org/10.1038/mp.2013.1
Publication status	Published - Nov 2013

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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., ... Lambert, J.-C. (2013). Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Molecular psychiatry, 18(11). https://doi.org/10.1038/mp.2013.1

@article{e636b8e16f7d44fcb3afb404c4ac0aed,

title = "Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.",

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.",

author = "J Chapuis and F Hansmannel and M Gistelinck and A Mounier and {Van Cauwenberghe}, C and Kolen, {K V} and F Geller and Y Sottejeau and D Harold and P Dourlen and B Grenier-Boley and Y Kamatani and B Delepine and F Demiautte and D Zelenika and N Zommer and M Hamdane and C Bellenguez and J-F Dartigues and J-J Hauw and F Letronne and A-M Ayral and K Sleegers and A Schellens and Broeck, {L V} and S Engelborghs and {De Deyn}, {P P} and R Vandenberghe and M O'Donovan and M Owen and J Epelbaum and M Mercken and E Karran and M Bantscheff and G Drewes and G Joberty and D Campion and J-N Octave and C Berr and M Lathrop and P Callaerts and D Mann and J Williams and L Bu{\'e}e and I Dewachter and {Van Broeckhoven}, C and P Amouyel and D Moechars and B Dermaut and J-C Lambert",

note = "G0902227, Medical Research Council, United Kingdom, Medical Research Council, United Kingdom, Wellcome Trust, United Kingdom",

year = "2013",

month = nov,

doi = "10.1038/mp.2013.1",

language = "English",

volume = "18",

journal = "Molecular psychiatry",

issn = "1476-5578",

publisher = "Springer Nature",

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}

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, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, 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, J-N, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, J, Buée, L, Dewachter, I, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B & Lambert, J-C 2013, 'Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.', Molecular psychiatry, vol. 18, no. 11. https://doi.org/10.1038/mp.2013.1

TY - JOUR

T1 - Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

AU - Chapuis, J

AU - Hansmannel, F

AU - Gistelinck, M

AU - Mounier, A

AU - Van Cauwenberghe, C

AU - Kolen, K V

AU - Geller, F

AU - Sottejeau, Y

AU - Harold, D

AU - Dourlen, P

AU - Grenier-Boley, B

AU - Kamatani, Y

AU - Delepine, B

AU - Demiautte, F

AU - Zelenika, D

AU - Zommer, N

AU - Hamdane, M

AU - Bellenguez, C

AU - Dartigues, J-F

AU - Hauw, J-J

AU - Letronne, F

AU - Ayral, A-M

AU - Sleegers, K

AU - Schellens, A

AU - Broeck, L V

AU - Engelborghs, S

AU - De Deyn, P P

AU - Vandenberghe, R

AU - O'Donovan, M

AU - Owen, M

AU - Epelbaum, J

AU - Mercken, M

AU - Karran, E

AU - Bantscheff, M

AU - Drewes, G

AU - Joberty, G

AU - Campion, D

AU - Octave, J-N

AU - Berr, C

AU - Lathrop, M

AU - Callaerts, P

AU - Mann, D

AU - Williams, J

AU - Buée, L

AU - Dewachter, I

AU - Van Broeckhoven, C

AU - Amouyel, P

AU - Moechars, D

AU - Dermaut, B

AU - Lambert, J-C

N1 - G0902227, Medical Research Council, United Kingdom, Medical Research Council, United Kingdom, Wellcome Trust, United Kingdom

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

U2 - 10.1038/mp.2013.1

DO - 10.1038/mp.2013.1

M3 - Article

C2 - 23399914

SN - 1476-5578

VL - 18

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 11

ER -

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

Abstract

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