Familial Alzheimer’s disease (FAD)–linked mutations in the APP gene occur either within the Aβ-coding region or immediately proximal and are located in exons 16 and 17, which encode Aβ peptides. We have identified an extremely rare, partially penetrant, single nucleotide variant (SNV), rs145081708, in APP that corresponds to a Ser198Pro substitution in exon 5. We now report that in stably transfected cells, expression of APP harboring the S198P mutation (APPS198P) leads to elevated production of Aβ peptides by an unconventional mechanism in which the folding and exit of APPS198P from the endoplasmic reticulum is accelerated. More importantly, coexpression of APP S198P and the FAD-linked PS1ΔE9 variant in the brains of male and female transgenic mice leads to elevated steady-state Aβ peptide levels and acceleration of Aβ deposition compared with age- and gender-matched mice expressing APP and PS1ΔE9. This is the first AD-linked mutation in APP present outside of exons 16 and 17 that enhances Aβ production and deposition.
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April 02 2021
An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo
Xulun Zhang
,
Xulun Zhang
Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Neurobiology, University of Chicago, Chicago, IL
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Can Martin Zhang
,
Can Martin Zhang
Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
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Dmitry Prokopenko
,
Dmitry Prokopenko
Formal analysis, Investigation, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
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Yingxia Liang
,
Yingxia Liang
Investigation, Resources, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
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Sherri Y. Zhen
,
Sherri Y. Zhen
Investigation
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
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Ian Q. Weigle
,
Ian Q. Weigle
Formal analysis, Investigation, Software, Writing - review & editing
1
Department of Neurobiology, University of Chicago, Chicago, IL
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Weinong Han
,
Weinong Han
Resources
1
Department of Neurobiology, University of Chicago, Chicago, IL
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Manish Aryal
,
Manish Aryal
Investigation
1
Department of Neurobiology, University of Chicago, Chicago, IL
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Rudolph E. Tanzi
,
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Visualization, Writing - original draft, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
Rudolph E. Tanzi: tanzi@helix.mgh.harvard.edu
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Sangram S. Sisodia
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Neurobiology, University of Chicago, Chicago, IL
Correspondence to Sangram S. Sisodia: ssisodia@bsd.uchicago.edu
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Xulun Zhang
Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Neurobiology, University of Chicago, Chicago, IL
Can Martin Zhang
Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Supervision, Validation, Visualization, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
Dmitry Prokopenko
Formal analysis, Investigation, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
Yingxia Liang
Investigation, Resources, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
Sherri Y. Zhen
Investigation
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
Ian Q. Weigle
Formal analysis, Investigation, Software, Writing - review & editing
1
Department of Neurobiology, University of Chicago, Chicago, IL
Weinong Han
Resources
1
Department of Neurobiology, University of Chicago, Chicago, IL
Manish Aryal
Investigation
1
Department of Neurobiology, University of Chicago, Chicago, IL
Rudolph E. Tanzi
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Visualization, Writing - original draft, Writing - review & editing
2
Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA
Sangram S. Sisodia
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Neurobiology, University of Chicago, Chicago, IL
Correspondence to Sangram S. Sisodia: ssisodia@bsd.uchicago.edu
Rudolph E. Tanzi: tanzi@helix.mgh.harvard.edu
Disclosures: The authors declare no competing interests exist.
Received:
February 07 2021
Revision Received:
March 03 2021
Accepted:
March 03 2021
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Cure Alzheimer's Fund
(NO AWARD)
© 2021 Zhang et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (6): e20210313.
Article history
Received:
February 07 2021
Revision Received:
March 03 2021
Accepted:
March 03 2021
Citation
Xulun Zhang, Can Martin Zhang, Dmitry Prokopenko, Yingxia Liang, Sherri Y. Zhen, Ian Q. Weigle, Weinong Han, Manish Aryal, Rudolph E. Tanzi, Sangram S. Sisodia; An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo. J Exp Med 7 June 2021; 218 (6): e20210313. doi: https://doi.org/10.1084/jem.20210313
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