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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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 languageEnglish
Article number100292
Number of pages15
JournalThe Journal of Biological Chemistry
Early online date14 Jan 2021
Publication statusPublished - 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.


  • 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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