Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

Nikolay  Solovyev; Ahmed H.  El-Khatib; Marta  Costas Rodríguez; Karima Schwab; Elizabeth Griffin; Andrea Raab; Bettina Riedel; Franz Theuring; Jochen Vogl; Frank Vanhaecke

doi:10.1016/j.jbc.2021.100292

Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

Nikolay Solovyev, Ahmed H. El-Khatib, Marta Costas Rodríguez, Karima Schwab, Elizabeth Griffin, Andrea Raab, Bettina Riedel, Franz Theuring, Jochen Vogl, Frank Vanhaecke^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Alzheimer’s disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. In AD, a distorted brain redox homeostasis and complexation by amyloid-beta and hyperphosphorylated tau may alter the iso- topic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the ho- meostasis of these elements. We used inductively coupled plasma–mass spectrometry (ICP-MS)-based techniques to determine the total Cu, Fe, and Zn contents in the brain, as well as their isotopic compositions in both mouse brain and serum. Results for male transgenic tau (Line 66, L66) and amyloid/ presenilin (5xFAD) mice were compared with those for the corresponding age- and sex-matched wild-type control mice (WT). Our data show that L66 brains showed significantly higher Fe levels than did those from the corresponding WT. Significantly less Cu, but more Zn was found in 5xFAD brains. We observed significantly lighter isotopic compositions of Fe (enrichment in the lighter isotopes) in the brain and serum of L66 mice compared with WT. For 5xFAD mice, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu. Our findings indicate significant pathology- specific alterations of Fe and Zn brain homeostasis in mouse models of AD. The associated changes in isotopic composition may serve as a marker for proteinopathies underlying AD and other types of dementia.

Original language	English
Article number	100292
Number of pages	15
Journal	The Journal of Biological Chemistry
Volume	296
Early online date	14 Jan 2021
DOIs	https://doi.org/10.1016/j.jbc.2021.100292
Publication status	Published - Jan 2021

Bibliographical note

Acknowledgments—A.H.E-K thanks Maren Koenig and Dorit Becker for their support in sample preparation. The authors thank Prof. Gernot Riedel, Dr Silke Frahm, and Mandy Magbagbeolu for help with mouse perfusion and harvesting of the brain tissues.
Funding and additional information—This work was carried out in the context of the EMPIR research project 15HLT02 (ReMiND). This project has received funding from the EMPIR programme cofinanced by the Participating States and from the European Union’s Horizon 2020 research and innovation program.

Keywords

Alzheimer's disease
tau
amyloid beta
copper
iron
zinc
multicollector inductively coupled plasma-mass spectrometry (ICP-MS)
brain
serum
isotopic analysis

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Solovyev, N., El-Khatib, A. H., Costas Rodríguez, M., Schwab, K., Griffin, E., Raab, A., Riedel, B., Theuring, F., Vogl, J., & Vanhaecke, F. (2021). Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy. The Journal of Biological Chemistry, 296, [100292]. https://doi.org/10.1016/j.jbc.2021.100292

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title = "Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy",

abstract = "Alzheimer{\textquoteright}s disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. In AD, a distorted brain redox homeostasis and complexation by amyloid-beta and hyperphosphorylated tau may alter the iso- topic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the ho- meostasis of these elements. We used inductively coupled plasma–mass spectrometry (ICP-MS)-based techniques to determine the total Cu, Fe, and Zn contents in the brain, as well as their isotopic compositions in both mouse brain and serum. Results for male transgenic tau (Line 66, L66) and amyloid/ presenilin (5xFAD) mice were compared with those for the corresponding age- and sex-matched wild-type control mice (WT). Our data show that L66 brains showed significantly higher Fe levels than did those from the corresponding WT. Significantly less Cu, but more Zn was found in 5xFAD brains. We observed significantly lighter isotopic compositions of Fe (enrichment in the lighter isotopes) in the brain and serum of L66 mice compared with WT. For 5xFAD mice, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu. Our findings indicate significant pathology- specific alterations of Fe and Zn brain homeostasis in mouse models of AD. The associated changes in isotopic composition may serve as a marker for proteinopathies underlying AD and other types of dementia.",

keywords = "Alzheimer's disease, tau, amyloid beta, copper, iron, zinc, multicollector inductively coupled plasma-mass spectrometry (ICP-MS), brain, serum, isotopic analysis",

author = "Nikolay Solovyev and El-Khatib, {Ahmed H.} and {Costas Rodr{\'i}guez}, Marta and Karima Schwab and Elizabeth Griffin and Andrea Raab and Bettina Riedel and Franz Theuring and Jochen Vogl and Frank Vanhaecke",

note = "Acknowledgments—A.H.E-K thanks Maren Koenig and Dorit Becker for their support in sample preparation. The authors thank Prof. Gernot Riedel, Dr Silke Frahm, and Mandy Magbagbeolu for help with mouse perfusion and harvesting of the brain tissues. Funding and additional information—This work was carried out in the context of the EMPIR research project 15HLT02 (ReMiND). This project has received funding from the EMPIR programme cofinanced by the Participating States and from the European Union{\textquoteright}s Horizon 2020 research and innovation program.",

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T1 - Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

AU - Solovyev, Nikolay

AU - El-Khatib, Ahmed H.

AU - Costas Rodríguez, Marta

AU - Schwab, Karima

AU - Griffin, Elizabeth

AU - Raab, Andrea

AU - Riedel, Bettina

AU - Theuring, Franz

AU - Vogl, Jochen

AU - Vanhaecke, Frank

N1 - Acknowledgments—A.H.E-K thanks Maren Koenig and Dorit Becker for their support in sample preparation. The authors thank Prof. Gernot Riedel, Dr Silke Frahm, and Mandy Magbagbeolu for help with mouse perfusion and harvesting of the brain tissues. Funding and additional information—This work was carried out in the context of the EMPIR research project 15HLT02 (ReMiND). This project has received funding from the EMPIR programme cofinanced by the Participating States and from the European Union’s Horizon 2020 research and innovation program.

PY - 2021/1

Y1 - 2021/1

N2 - Alzheimer’s disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. In AD, a distorted brain redox homeostasis and complexation by amyloid-beta and hyperphosphorylated tau may alter the iso- topic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the ho- meostasis of these elements. We used inductively coupled plasma–mass spectrometry (ICP-MS)-based techniques to determine the total Cu, Fe, and Zn contents in the brain, as well as their isotopic compositions in both mouse brain and serum. Results for male transgenic tau (Line 66, L66) and amyloid/ presenilin (5xFAD) mice were compared with those for the corresponding age- and sex-matched wild-type control mice (WT). Our data show that L66 brains showed significantly higher Fe levels than did those from the corresponding WT. Significantly less Cu, but more Zn was found in 5xFAD brains. We observed significantly lighter isotopic compositions of Fe (enrichment in the lighter isotopes) in the brain and serum of L66 mice compared with WT. For 5xFAD mice, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu. Our findings indicate significant pathology- specific alterations of Fe and Zn brain homeostasis in mouse models of AD. The associated changes in isotopic composition may serve as a marker for proteinopathies underlying AD and other types of dementia.

AB - Alzheimer’s disease (AD) is characterized by accumulation of tau and amyloid-beta in the brain, and recent evidence suggests a correlation between associated protein aggregates and trace elements, such as copper, iron, and zinc. In AD, a distorted brain redox homeostasis and complexation by amyloid-beta and hyperphosphorylated tau may alter the iso- topic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the ho- meostasis of these elements. We used inductively coupled plasma–mass spectrometry (ICP-MS)-based techniques to determine the total Cu, Fe, and Zn contents in the brain, as well as their isotopic compositions in both mouse brain and serum. Results for male transgenic tau (Line 66, L66) and amyloid/ presenilin (5xFAD) mice were compared with those for the corresponding age- and sex-matched wild-type control mice (WT). Our data show that L66 brains showed significantly higher Fe levels than did those from the corresponding WT. Significantly less Cu, but more Zn was found in 5xFAD brains. We observed significantly lighter isotopic compositions of Fe (enrichment in the lighter isotopes) in the brain and serum of L66 mice compared with WT. For 5xFAD mice, Zn exhibited a trend toward a lighter isotopic composition in the brain and a heavier isotopic composition in serum compared with WT. Neither mouse model yielded differences in the isotopic composition of Cu. Our findings indicate significant pathology- specific alterations of Fe and Zn brain homeostasis in mouse models of AD. The associated changes in isotopic composition may serve as a marker for proteinopathies underlying AD and other types of dementia.

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KW - iron

KW - zinc

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KW - serum

KW - isotopic analysis

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JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

M1 - 100292

ER -

Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

Abstract

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Keywords

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