BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology

Sandra Caecilie Signore; Fred Silvester Wouters; Matthias Schmitz; Mathias Baehr; Pawel Kermer

doi:doi:10.11648/j.ajpn.20210902.18

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BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology

Sandra Caecilie Signore, Fred Silvester Wouters, Matthias Schmitz, Mathias Baehr, Pawel Kermer

Published in American Journal of Psychiatry and Neuroscience (Volume 9, Issue 2)

Received: 2 June 2021 Accepted: 16 June 2021 Published: 23 June 2021

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Abstract

The Bcl-2-associated athanogene-1 (BAG1) exerts neuroprotective properties which has been shown in several studies of neurodegenerative disease models like Parkinson’s disease, Huntington’s disease and even cerebral ischemia. On the basis of the well-known neuroprotective function of the co-chaperone, we wanted to examine its properties in a model for Alzheimer’s disease, a neurological disorder of great significance. One of the hallmarks of Alzheimer’s disease, besides extracellular plaque formation, is the intra-neuronal accumulation of hyper-phosphorylated tau protein that leads to tau aggregation. When overexpressed together with a tau mutant with high propensity for aggregation, BAG1 led to the stabilization of high-molecular tau fragments in rat CSM 14.1 cells compared to wild-type cells. Deletion of the domain in BAG1 that is responsible for binding to Hsp70 (BAGΔC) abolished this effect, which could be confirmed by immunocytochemistry. In fact, BAG1 does not only increase mutant tau aggregation but also prevents its degradation by the proteasome. Immunochemistry revealed that overexpression of the Bcl-2-associated athanogene-1 gives rise to large tau aggregates surrounded by lysosomes. Furthermore, toxicity assays indicated increased tau toxicity in BAG1 overexpressing cells. Hence, in contrast to other neurodegenerative diseases, BAG1 seems to enhance Alzheimer´s pathology and to promote cell death due to the stabilization of aggregation-prone tau species that evade proteasomal clearance. To conclude, this analysis provides a new sight of the co-chaperone BAG1 and yet again demonstrates its complex influence in a model of Alzheimer’s disease.

Published in	American Journal of Psychiatry and Neuroscience (Volume 9, Issue 2)
DOI	10.11648/j.ajpn.20210902.18
Page(s)	77-85
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2021. Published by Science Publishing Group

Keywords

Alzheimer’s Pathology, BAG1, Tau Protein, Co-chaperone, Neurodegeneration

References

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APA Style

Sandra Caecilie Signore, Fred Silvester Wouters, Matthias Schmitz, Mathias Baehr, Pawel Kermer. (2021). BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology. American Journal of Psychiatry and Neuroscience, 9(2), 77-85. https://doi.org/10.11648/j.ajpn.20210902.18

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ACS Style

Sandra Caecilie Signore; Fred Silvester Wouters; Matthias Schmitz; Mathias Baehr; Pawel Kermer. BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology. Am. J. Psychiatry Neurosci. 2021, 9(2), 77-85. doi: 10.11648/j.ajpn.20210902.18

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AMA Style

Sandra Caecilie Signore, Fred Silvester Wouters, Matthias Schmitz, Mathias Baehr, Pawel Kermer. BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology. Am J Psychiatry Neurosci. 2021;9(2):77-85. doi: 10.11648/j.ajpn.20210902.18

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@article{10.11648/j.ajpn.20210902.18,
  author = {Sandra Caecilie Signore and Fred Silvester Wouters and Matthias Schmitz and Mathias Baehr and Pawel Kermer},
  title = {BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology},
  journal = {American Journal of Psychiatry and Neuroscience},
  volume = {9},
  number = {2},
  pages = {77-85},
  doi = {10.11648/j.ajpn.20210902.18},
  url = {https://doi.org/10.11648/j.ajpn.20210902.18},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajpn.20210902.18},
  abstract = {The Bcl-2-associated athanogene-1 (BAG1) exerts neuroprotective properties which has been shown in several studies of neurodegenerative disease models like Parkinson’s disease, Huntington’s disease and even cerebral ischemia. On the basis of the well-known neuroprotective function of the co-chaperone, we wanted to examine its properties in a model for Alzheimer’s disease, a neurological disorder of great significance. One of the hallmarks of Alzheimer’s disease, besides extracellular plaque formation, is the intra-neuronal accumulation of hyper-phosphorylated tau protein that leads to tau aggregation. When overexpressed together with a tau mutant with high propensity for aggregation, BAG1 led to the stabilization of high-molecular tau fragments in rat CSM 14.1 cells compared to wild-type cells. Deletion of the domain in BAG1 that is responsible for binding to Hsp70 (BAGΔC) abolished this effect, which could be confirmed by immunocytochemistry. In fact, BAG1 does not only increase mutant tau aggregation but also prevents its degradation by the proteasome. Immunochemistry revealed that overexpression of the Bcl-2-associated athanogene-1 gives rise to large tau aggregates surrounded by lysosomes. Furthermore, toxicity assays indicated increased tau toxicity in BAG1 overexpressing cells. Hence, in contrast to other neurodegenerative diseases, BAG1 seems to enhance Alzheimer´s pathology and to promote cell death due to the stabilization of aggregation-prone tau species that evade proteasomal clearance. To conclude, this analysis provides a new sight of the co-chaperone BAG1 and yet again demonstrates its complex influence in a model of Alzheimer’s disease.},
 year = {2021}
}

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TY  - JOUR
T1  - BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology
AU  - Sandra Caecilie Signore
AU  - Fred Silvester Wouters
AU  - Matthias Schmitz
AU  - Mathias Baehr
AU  - Pawel Kermer
Y1  - 2021/06/23
PY  - 2021
N1  - https://doi.org/10.11648/j.ajpn.20210902.18
DO  - 10.11648/j.ajpn.20210902.18
T2  - American Journal of Psychiatry and Neuroscience
JF  - American Journal of Psychiatry and Neuroscience
JO  - American Journal of Psychiatry and Neuroscience
SP  - 77
EP  - 85
PB  - Science Publishing Group
SN  - 2330-426X
UR  - https://doi.org/10.11648/j.ajpn.20210902.18
AB  - The Bcl-2-associated athanogene-1 (BAG1) exerts neuroprotective properties which has been shown in several studies of neurodegenerative disease models like Parkinson’s disease, Huntington’s disease and even cerebral ischemia. On the basis of the well-known neuroprotective function of the co-chaperone, we wanted to examine its properties in a model for Alzheimer’s disease, a neurological disorder of great significance. One of the hallmarks of Alzheimer’s disease, besides extracellular plaque formation, is the intra-neuronal accumulation of hyper-phosphorylated tau protein that leads to tau aggregation. When overexpressed together with a tau mutant with high propensity for aggregation, BAG1 led to the stabilization of high-molecular tau fragments in rat CSM 14.1 cells compared to wild-type cells. Deletion of the domain in BAG1 that is responsible for binding to Hsp70 (BAGΔC) abolished this effect, which could be confirmed by immunocytochemistry. In fact, BAG1 does not only increase mutant tau aggregation but also prevents its degradation by the proteasome. Immunochemistry revealed that overexpression of the Bcl-2-associated athanogene-1 gives rise to large tau aggregates surrounded by lysosomes. Furthermore, toxicity assays indicated increased tau toxicity in BAG1 overexpressing cells. Hence, in contrast to other neurodegenerative diseases, BAG1 seems to enhance Alzheimer´s pathology and to promote cell death due to the stabilization of aggregation-prone tau species that evade proteasomal clearance. To conclude, this analysis provides a new sight of the co-chaperone BAG1 and yet again demonstrates its complex influence in a model of Alzheimer’s disease.
VL  - 9
IS  - 2
ER  -

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Author Information

Sandra Caecilie Signore

Department of Neurology, University Hospital Goettingen, Goettingen, Germany
Fred Silvester Wouters

Laboratory for Molecular and Cellular Systems, Department of Neuropathology, University Medical Center, Goettingen, Germany
Matthias Schmitz

Department of Neurology, University Medical Center G?ttingen and the German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany
Mathias Baehr

Department of Neurology, University Hospital Goettingen, Goettingen, Germany
Pawel Kermer

Department of Neurology, University Hospital Goettingen, Goettingen, Germany

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Sandra Caecilie Signore, Fred Silvester Wouters, Matthias Schmitz, Mathias Baehr, Pawel Kermer. (2021). BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology. American Journal of Psychiatry and Neuroscience, 9(2), 77-85. https://doi.org/10.11648/j.ajpn.20210902.18

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ACS Style

Sandra Caecilie Signore; Fred Silvester Wouters; Matthias Schmitz; Mathias Baehr; Pawel Kermer. BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology. Am. J. Psychiatry Neurosci. 2021, 9(2), 77-85. doi: 10.11648/j.ajpn.20210902.18

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AMA Style

Sandra Caecilie Signore, Fred Silvester Wouters, Matthias Schmitz, Mathias Baehr, Pawel Kermer. BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology. Am J Psychiatry Neurosci. 2021;9(2):77-85. doi: 10.11648/j.ajpn.20210902.18

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@article{10.11648/j.ajpn.20210902.18,
  author = {Sandra Caecilie Signore and Fred Silvester Wouters and Matthias Schmitz and Mathias Baehr and Pawel Kermer},
  title = {BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology},
  journal = {American Journal of Psychiatry and Neuroscience},
  volume = {9},
  number = {2},
  pages = {77-85},
  doi = {10.11648/j.ajpn.20210902.18},
  url = {https://doi.org/10.11648/j.ajpn.20210902.18},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajpn.20210902.18},
  abstract = {The Bcl-2-associated athanogene-1 (BAG1) exerts neuroprotective properties which has been shown in several studies of neurodegenerative disease models like Parkinson’s disease, Huntington’s disease and even cerebral ischemia. On the basis of the well-known neuroprotective function of the co-chaperone, we wanted to examine its properties in a model for Alzheimer’s disease, a neurological disorder of great significance. One of the hallmarks of Alzheimer’s disease, besides extracellular plaque formation, is the intra-neuronal accumulation of hyper-phosphorylated tau protein that leads to tau aggregation. When overexpressed together with a tau mutant with high propensity for aggregation, BAG1 led to the stabilization of high-molecular tau fragments in rat CSM 14.1 cells compared to wild-type cells. Deletion of the domain in BAG1 that is responsible for binding to Hsp70 (BAGΔC) abolished this effect, which could be confirmed by immunocytochemistry. In fact, BAG1 does not only increase mutant tau aggregation but also prevents its degradation by the proteasome. Immunochemistry revealed that overexpression of the Bcl-2-associated athanogene-1 gives rise to large tau aggregates surrounded by lysosomes. Furthermore, toxicity assays indicated increased tau toxicity in BAG1 overexpressing cells. Hence, in contrast to other neurodegenerative diseases, BAG1 seems to enhance Alzheimer´s pathology and to promote cell death due to the stabilization of aggregation-prone tau species that evade proteasomal clearance. To conclude, this analysis provides a new sight of the co-chaperone BAG1 and yet again demonstrates its complex influence in a model of Alzheimer’s disease.},
 year = {2021}
}

Copy | Download

TY  - JOUR
T1  - BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology
AU  - Sandra Caecilie Signore
AU  - Fred Silvester Wouters
AU  - Matthias Schmitz
AU  - Mathias Baehr
AU  - Pawel Kermer
Y1  - 2021/06/23
PY  - 2021
N1  - https://doi.org/10.11648/j.ajpn.20210902.18
DO  - 10.11648/j.ajpn.20210902.18
T2  - American Journal of Psychiatry and Neuroscience
JF  - American Journal of Psychiatry and Neuroscience
JO  - American Journal of Psychiatry and Neuroscience
SP  - 77
EP  - 85
PB  - Science Publishing Group
SN  - 2330-426X
UR  - https://doi.org/10.11648/j.ajpn.20210902.18
AB  - The Bcl-2-associated athanogene-1 (BAG1) exerts neuroprotective properties which has been shown in several studies of neurodegenerative disease models like Parkinson’s disease, Huntington’s disease and even cerebral ischemia. On the basis of the well-known neuroprotective function of the co-chaperone, we wanted to examine its properties in a model for Alzheimer’s disease, a neurological disorder of great significance. One of the hallmarks of Alzheimer’s disease, besides extracellular plaque formation, is the intra-neuronal accumulation of hyper-phosphorylated tau protein that leads to tau aggregation. When overexpressed together with a tau mutant with high propensity for aggregation, BAG1 led to the stabilization of high-molecular tau fragments in rat CSM 14.1 cells compared to wild-type cells. Deletion of the domain in BAG1 that is responsible for binding to Hsp70 (BAGΔC) abolished this effect, which could be confirmed by immunocytochemistry. In fact, BAG1 does not only increase mutant tau aggregation but also prevents its degradation by the proteasome. Immunochemistry revealed that overexpression of the Bcl-2-associated athanogene-1 gives rise to large tau aggregates surrounded by lysosomes. Furthermore, toxicity assays indicated increased tau toxicity in BAG1 overexpressing cells. Hence, in contrast to other neurodegenerative diseases, BAG1 seems to enhance Alzheimer´s pathology and to promote cell death due to the stabilization of aggregation-prone tau species that evade proteasomal clearance. To conclude, this analysis provides a new sight of the co-chaperone BAG1 and yet again demonstrates its complex influence in a model of Alzheimer’s disease.
VL  - 9
IS  - 2
ER  -

Copy | Download