Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts

Pierre De Rossi; Virginie Buggia-Prévot; Benjamin L.L. Clayton; Jared B. Vasquez; Carson Van Sanford; Robert J. Andrew; Ruben Lesnick; Alexandra Botté; Carole Deyts; Someya Salem; Eshaan Rao; Richard C. Rice; Angèle Parent; Satyabrata Kar; Brian Popko; Peter Pytel; Steven Estus; Gopal Thinakaran

doi:10.1186/s13024-016-0124-1

Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts

Pierre De Rossi, Virginie Buggia-Prévot, Benjamin L.L. Clayton, Jared B. Vasquez, Carson Van Sanford, Robert J. Andrew, Ruben Lesnick, Alexandra Botté, Carole Deyts, Someya Salem, Eshaan Rao, Richard C. Rice, Angèle Parent, Satyabrata Kar, Brian Popko, Peter Pytel, Steven Estus, Gopal Thinakaran

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

59 Scopus citations

Abstract

Background: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD. Methods: In this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. Results: Here, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions. Conclusion: Our study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.

Original language	English
Article number	59
Journal	Molecular Neurodegeneration
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s13024-016-0124-1
State	Published - Aug 3 2016

Bibliographical note

Funding Information:
We thank the University of Kentucky AD Center Neuropathology Core for providing the human brain specimens used for RNA analysis. Postmortem tissue specimens for biochemical analysis were provided by NIH Neurobiobank through the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, and the Department of Veterans Administration. We thank the Histology Core Facility at the University of Chicago Human Tissue Resource Center for immunostaining of human tissue. We thank Dr. Manuel F. Utset for helpful suggestions during the course of this study.

Funding Information:
This study was supported by Cure Alzheimer’s Fund (GT), National Multiple Sclerosis Society and Illinois Department of Public Health Multiple Sclerosis Research Fund Grant (GT), BrightFocus Foundation (SE), and National Institutes of Health grants AG019070 (GT), AG045775 (SE), and NS034939 (PB). P.D.R. was supported by an AD Research fellowship from the Illinois Department of Public Health and V.B.P was supported by a postdoctoral fellowship from BrightFocus Foundation. C.V.S. was supported by the National Center for Advancing Translational Sciences grant UL1TR000117. The authors acknowledge the University of Kentucky Alzheimer’s Center (supported by P30-AG028383) for human tissue samples. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10OD010649). The use of University of Chicago’s Core Facilities was supported by the National Center For Advancing Translational Sciences Award 5 UL1 TR 000430–09.

Publisher Copyright:
© 2016 The Author(s).

Keywords

Alternative splicing
Alzheimer's disease
Amphiphysin 1
BIN1
Immunohistochemistry
Isoform diversity
Late-onset Alzheimer's disease
Multiple sclerosis
Myelination
Oligodendrocyte

ASJC Scopus subject areas

Molecular Biology
Clinical Neurology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13024-016-0124-1

Cite this

De Rossi, P., Buggia-Prévot, V., Clayton, B. L. L., Vasquez, J. B., Van Sanford, C., Andrew, R. J., Lesnick, R., Botté, A., Deyts, C., Salem, S., Rao, E., Rice, R. C., Parent, A., Kar, S., Popko, B., Pytel, P., Estus, S., & Thinakaran, G. (2016). Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Molecular Neurodegeneration, 11(1), [59]. https://doi.org/10.1186/s13024-016-0124-1

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title = "Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts",

abstract = "Background: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD. Methods: In this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. Results: Here, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions. Conclusion: Our study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.",

keywords = "Alternative splicing, Alzheimer's disease, Amphiphysin 1, BIN1, Immunohistochemistry, Isoform diversity, Late-onset Alzheimer's disease, Multiple sclerosis, Myelination, Oligodendrocyte",

author = "{De Rossi}, Pierre and Virginie Buggia-Pr{\'e}vot and Clayton, {Benjamin L.L.} and Vasquez, {Jared B.} and {Van Sanford}, Carson and Andrew, {Robert J.} and Ruben Lesnick and Alexandra Bott{\'e} and Carole Deyts and Someya Salem and Eshaan Rao and Rice, {Richard C.} and Ang{\`e}le Parent and Satyabrata Kar and Brian Popko and Peter Pytel and Steven Estus and Gopal Thinakaran",

note = "Funding Information: We thank the University of Kentucky AD Center Neuropathology Core for providing the human brain specimens used for RNA analysis. Postmortem tissue specimens for biochemical analysis were provided by NIH Neurobiobank through the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, and the Department of Veterans Administration. We thank the Histology Core Facility at the University of Chicago Human Tissue Resource Center for immunostaining of human tissue. We thank Dr. Manuel F. Utset for helpful suggestions during the course of this study. Funding Information: This study was supported by Cure Alzheimer{\textquoteright}s Fund (GT), National Multiple Sclerosis Society and Illinois Department of Public Health Multiple Sclerosis Research Fund Grant (GT), BrightFocus Foundation (SE), and National Institutes of Health grants AG019070 (GT), AG045775 (SE), and NS034939 (PB). P.D.R. was supported by an AD Research fellowship from the Illinois Department of Public Health and V.B.P was supported by a postdoctoral fellowship from BrightFocus Foundation. C.V.S. was supported by the National Center for Advancing Translational Sciences grant UL1TR000117. The authors acknowledge the University of Kentucky Alzheimer{\textquoteright}s Center (supported by P30-AG028383) for human tissue samples. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10OD010649). The use of University of Chicago{\textquoteright}s Core Facilities was supported by the National Center For Advancing Translational Sciences Award 5 UL1 TR 000430–09. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

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month = aug,

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doi = "10.1186/s13024-016-0124-1",

language = "English",

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De Rossi, P, Buggia-Prévot, V, Clayton, BLL, Vasquez, JB, Van Sanford, C, Andrew, RJ, Lesnick, R, Botté, A, Deyts, C, Salem, S, Rao, E, Rice, RC, Parent, A, Kar, S, Popko, B, Pytel, P, Estus, S & Thinakaran, G 2016, 'Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts', Molecular Neurodegeneration, vol. 11, no. 1, 59. https://doi.org/10.1186/s13024-016-0124-1

TY - JOUR

T1 - Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts

AU - De Rossi, Pierre

AU - Buggia-Prévot, Virginie

AU - Clayton, Benjamin L.L.

AU - Vasquez, Jared B.

AU - Van Sanford, Carson

AU - Andrew, Robert J.

AU - Lesnick, Ruben

AU - Botté, Alexandra

AU - Deyts, Carole

AU - Salem, Someya

AU - Rao, Eshaan

AU - Rice, Richard C.

AU - Parent, Angèle

AU - Kar, Satyabrata

AU - Popko, Brian

AU - Pytel, Peter

AU - Estus, Steven

AU - Thinakaran, Gopal

N1 - Funding Information: We thank the University of Kentucky AD Center Neuropathology Core for providing the human brain specimens used for RNA analysis. Postmortem tissue specimens for biochemical analysis were provided by NIH Neurobiobank through the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, and the Department of Veterans Administration. We thank the Histology Core Facility at the University of Chicago Human Tissue Resource Center for immunostaining of human tissue. We thank Dr. Manuel F. Utset for helpful suggestions during the course of this study. Funding Information: This study was supported by Cure Alzheimer’s Fund (GT), National Multiple Sclerosis Society and Illinois Department of Public Health Multiple Sclerosis Research Fund Grant (GT), BrightFocus Foundation (SE), and National Institutes of Health grants AG019070 (GT), AG045775 (SE), and NS034939 (PB). P.D.R. was supported by an AD Research fellowship from the Illinois Department of Public Health and V.B.P was supported by a postdoctoral fellowship from BrightFocus Foundation. C.V.S. was supported by the National Center for Advancing Translational Sciences grant UL1TR000117. The authors acknowledge the University of Kentucky Alzheimer’s Center (supported by P30-AG028383) for human tissue samples. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10OD010649). The use of University of Chicago’s Core Facilities was supported by the National Center For Advancing Translational Sciences Award 5 UL1 TR 000430–09. Publisher Copyright: © 2016 The Author(s).

PY - 2016/8/3

Y1 - 2016/8/3

N2 - Background: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD. Methods: In this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. Results: Here, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions. Conclusion: Our study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.

AB - Background: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD. Methods: In this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. Results: Here, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions. Conclusion: Our study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.

KW - Alternative splicing

KW - Alzheimer's disease

KW - Amphiphysin 1

KW - BIN1

KW - Immunohistochemistry

KW - Isoform diversity

KW - Late-onset Alzheimer's disease

KW - Multiple sclerosis

KW - Myelination

KW - Oligodendrocyte

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Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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