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 Platt,Franz Theuring,Jochen Vogl,Frank Vanhaecke

doi:10.1016/j.jbc.2021.100292

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 isotopic composition of essential mineral elements. Therefore, high-precision isotopic analysis may reveal changes in the homeostasis 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.

Highlights

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
Analytical methods applied in the different research facilities involved were evaluated and thereafter implemented for the traceable quantitative determination and for the accurate and precise isotopic analysis of Cu, Fe, and Zn in the brain tissue and blood serum of Line 66 (L66) and 5xFAD mice, as well as of their respective controls
L66 mice and their NMRI wild-type (NMRI-wild-type control mice (WT)) controls received the same chow (V1534-3) for the first 10 months, but between 10 and 12 months L66 received a different chow with higher protein content (V1124–3) because they developed a considerable tremor

Summary

Introduction

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. Hyperphosphorylated tau, a microtubule-associated protein, leads to the formation of neurofibrillary tangles, composed of a truncated 100-amino acid fragment of tau [6], which can autonomously catalyze the conversion of normal soluble tau into tau fibrils and tau aggregates [7] Both tau and Aβ aggregation contribute to AD pathology, but hypotheses differ as to which of these is the primary causative factor [8]. More mechanistic studies indicate several possible pathways relating Cu, Fe, and Zn with AD pathology [18,19,20]

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Results

Conclusion