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The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method

Evidence suggests that β-secretase (BACE1), which cleaves Amyloid Precursor Protein (APP) to form sAPPβ and amyloid-β, is elevated in Alzheimer's disease (AD) brains and biofluids and, thus, BACE1 is a therapeutic target for this devastating disease. The direct product of BACE1 cleavage of APP,...

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Autores principales: Dobrowolska Zakaria, Justyna A., Bateman, Randall J., Lysakowska, Monika, Khatri, Ammaarah, Jean-Gilles, Dinorah, Kennedy, Matthew E., Vassar, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440206/
https://www.ncbi.nlm.nih.gov/pubmed/36056033
http://dx.doi.org/10.1038/s41598-022-18869-3
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author Dobrowolska Zakaria, Justyna A.
Bateman, Randall J.
Lysakowska, Monika
Khatri, Ammaarah
Jean-Gilles, Dinorah
Kennedy, Matthew E.
Vassar, Robert
author_facet Dobrowolska Zakaria, Justyna A.
Bateman, Randall J.
Lysakowska, Monika
Khatri, Ammaarah
Jean-Gilles, Dinorah
Kennedy, Matthew E.
Vassar, Robert
author_sort Dobrowolska Zakaria, Justyna A.
collection PubMed
description Evidence suggests that β-secretase (BACE1), which cleaves Amyloid Precursor Protein (APP) to form sAPPβ and amyloid-β, is elevated in Alzheimer's disease (AD) brains and biofluids and, thus, BACE1 is a therapeutic target for this devastating disease. The direct product of BACE1 cleavage of APP, sAPPβ, serves as a surrogate marker of BACE1 activity in the central nervous system. This biomarker could be utilized to better understand normal APP processing, aberrant processing in the disease setting, and modulations to processing during therapeutic intervention. In this paper, we present a method for measuring the metabolism of sAPPβ and another APP proteolytic product, sAPPα, in vivo in humans using stable isotope labeling kinetics, paired with immunoprecipitation and liquid chromatography/tandem mass spectrometry. The method presented herein is robust, reproducible, and precise, and allows for the study of these analytes by taking into account their full dynamic potential as opposed to the traditional methods of absolute concentration quantitation that only provide a static view of a dynamic system. A study of in vivo cerebrospinal fluid sAPPβ and sAPPα kinetics using these methods could reveal novel insights into pathophysiological mechanisms of AD, such as increased BACE1 processing of APP.
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spelling pubmed-94402062022-09-04 The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method Dobrowolska Zakaria, Justyna A. Bateman, Randall J. Lysakowska, Monika Khatri, Ammaarah Jean-Gilles, Dinorah Kennedy, Matthew E. Vassar, Robert Sci Rep Article Evidence suggests that β-secretase (BACE1), which cleaves Amyloid Precursor Protein (APP) to form sAPPβ and amyloid-β, is elevated in Alzheimer's disease (AD) brains and biofluids and, thus, BACE1 is a therapeutic target for this devastating disease. The direct product of BACE1 cleavage of APP, sAPPβ, serves as a surrogate marker of BACE1 activity in the central nervous system. This biomarker could be utilized to better understand normal APP processing, aberrant processing in the disease setting, and modulations to processing during therapeutic intervention. In this paper, we present a method for measuring the metabolism of sAPPβ and another APP proteolytic product, sAPPα, in vivo in humans using stable isotope labeling kinetics, paired with immunoprecipitation and liquid chromatography/tandem mass spectrometry. The method presented herein is robust, reproducible, and precise, and allows for the study of these analytes by taking into account their full dynamic potential as opposed to the traditional methods of absolute concentration quantitation that only provide a static view of a dynamic system. A study of in vivo cerebrospinal fluid sAPPβ and sAPPα kinetics using these methods could reveal novel insights into pathophysiological mechanisms of AD, such as increased BACE1 processing of APP. Nature Publishing Group UK 2022-09-02 /pmc/articles/PMC9440206/ /pubmed/36056033 http://dx.doi.org/10.1038/s41598-022-18869-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dobrowolska Zakaria, Justyna A.
Bateman, Randall J.
Lysakowska, Monika
Khatri, Ammaarah
Jean-Gilles, Dinorah
Kennedy, Matthew E.
Vassar, Robert
The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
title The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
title_full The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
title_fullStr The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
title_full_unstemmed The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
title_short The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
title_sort metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440206/
https://www.ncbi.nlm.nih.gov/pubmed/36056033
http://dx.doi.org/10.1038/s41598-022-18869-3
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