4.4 Article

Longitudinal biometal accumulation and Ca isotope composition of the Gottingen minipig brain

Journal

METALLOMICS
Volume 12, Issue 10, Pages 1585-1598

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d0mt00134a

Keywords

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Funding

  1. European Research Council (ERC) under the European Community's H2020 framework program/ERC [637503 - Pristine]
  2. UnivEarthS Labex program at Universite de Paris
  3. IPGP multidisciplinary program PARI
  4. Region-ile-de-France SESAME [12015908]
  5. Macquarie University Deputy Vice Chancellor (DVCR) discretionary funds

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Biometals play a critical role in both the healthy and diseased brain's functioning. They accumulate in the normal aging brain, and are inherent to neurodegenerative disorders and their associated pathologies. A prominent example of this is the brain accumulation of metals such as Ca, Fe and Cu (and more ambiguously, Zn) associated with Alzheimer's disease (AD). The natural stable isotope compositions of such metals have also shown utility in constraining biological mechanisms, and in differentiating between healthy and diseased states, sometimes prior to conventional methods. Here we have detailed the distribution of the biologically relevant elements Mg, P, K, Ca, Fe, Cu and Zn in brain regions of Gottingen minipigs ranging in age from three months to nearly six years, including control animals and both a single- and double-transgenic model of AD (PS1, APP/PS1). Moreover, we have characterized the Ca isotope composition of the brain for the first time. Concentration data track rises in brain biometals with age, namely for Fe and Cu, as observed in the normal ageing brain and in AD, and biometal data point to increased soluble amyloid beta (A beta) load prior to AD plaque identificationviabrain imaging. Calcium isotope results define the brain as the isotopically lightest permanent reservoir in the body, indicating that brain Ca dyshomeostasis may induce measurable isotopic disturbances in accessible downstream reservoirs such as biofluids.

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