Serum and brain natural copper stable isotopes in a mouse model of Alzheimer’s disease

Abstract

Alzheimer’s disease is associated with the production of Cu rich aβ fibrils. Because monitoring the changes in Cu level of organs has been proposed to follow the evolution of the disease, we analyzed the copper isotopic composition of serum and brain of APPswe/PSEN1dE9 transgenic mice, a model of Alzheimer’s disease, and wild-type (WT) controls. Serum composition of 3, 6, 9 and 12-month-old mice, as well as the composition of 9 brains of 12-month-old mice are reported. In WT mice, brains were ~1‰ isotopically heavier than serum, and the Cu isotopic composition of the serum was isotopically different between males and females. We propose that this effect of sex on the Cu isotopic budget of the serum may be related to a difference of Cu speciation and relative abundance of Cu carriers. Brains of APPswe/PSEN1dE9 mice were slightly lighter than brains of WT mice, while not statistically significant. This trend may reflect an increase of Cu(I) associated with the formation of Aβ fibrils. The Cu isotopic composition of the brains and serum were correlated, implying copper transport between these two reservoirs, in particular a transfer of Cu(I) from the brain to the serum. Altogether, these data suggest that Cu stable isotopic composition of body fluid may have the potential to be used as detection tools for the formation of Aβ fibrils in the brain, but further work has to be done.

Copper and zinc isotopic excursions in the human brain affected by Alzheimer's disease

“…The copper isotopic composition of 19 samples (9 AD) and the zinc isotopic composition of 18 samples (9 AD) were possible to measure. The copper isotopic composition of human brains (average δ 65 Cu = +0.60 ± 0.13, for controls) falls within what was measured for mouse brain (+0.56 ± 0.28 for controls, 18 ). Human brain is therefore enriched in the heavy isotope of copper compared to serum (δ 65 Cu = 0.10 ± 0.22, 12 ), as observed in mice 18 .…”

High‐precision isotopic analysis of essential mineral elements: capabilities as a diagnostic/prognostic tool

“…Efforts should also no longer be solely exploratory, aiming at revealing possible differences between the isotopic composition of one or more essential mineral elements between patients and an appropriate reference population, but should also focus on identifying and understanding the factors driving these changes in isotopic composition, as this will bring clinical confidence and move the field away from an interesting but somewhat curious novelty. Obtaining a profound insight will entail the use of in vitro cell experiments, 12,33,41,52,61 in vivo experiments with animals, 11,28,34,45,46,48‐50,62, 63 and theoretical calculations 64–67 and the studies will have to be executed by interdisciplinary teams. For this unraveling of the factors governing the isotopic composition of essential mineral elements in various body compartments and in health and disease, complex processes will also have to be “dissected” and isotope fractionation needs to be studied on the level of subcellular compartments, 52 and on that of individual processes involving specific proteins or protein fractions 36,51,53 …”

“…Unfortunately, the isotopic composition of Zn in blood was not significantly affected upon development of AD, thus limiting diagnostic possibilities. In a later paper, Moynier et al 49 also studied the isotopic compositions of Cu in brains and serum of APPswe/PSEN1dE9 mice versus wild‐type mice, because Cu is involved in the formation of Aβ fibrils. No significant differences in Cu isotopic composition could be established.…”

Inter-comparison of stable iron, copper and zinc isotopic compositions in six reference materials of biological origin

“…The blood Cu isotopic composition has been shown to become lighter during ageing in a remote human Yakut population [25], and experiments on ageing C. elegans have confirmed this finding [26]. Copper isotopic compositions are highly sensible to disease conditions and have been investigated as a new biomarker for Wilson disease [27,28], cancer [29,30], liver diseases [24,31] and neurodegenerative disorders [32][33][34][35].…”