Alzheimer's Disease and Age-Related Changes in the Cu Isotopic Composition of Blood Plasma and Brain Tissues of the APPNL-G-F Murine Model Revealed by Multi-Collector ICP-Mass Spectrometry.

Abstract

Alzheimer's' disease (AD) is characterized by the formation of β-amyloid (Aβ) plaques and neurofibrillary tangles of tau protein in the brain. Aβ plaques are formed by the cleavage of the β-amyloid precursor protein (APP). In addition to protein aggregations, the metabolism of the essential mineral element Cu is also altered during the pathogenesis of AD. The concentration and the natural isotopic composition of Cu were investigated in blood plasma and multiple brain regions (brain stem, cerebellum, cortex, and hippocampus) of young (3-4 weeks) and aged (27-30 weeks) APPNL-G-F knock-in mice and wild-type controls to assess potential alterations associated with ageing and AD. Tandem inductively coupled plasma-mass spectrometry (ICP-MS/MS) was used for elemental analysis and multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS) for high-precision isotopic analysis. The blood plasma Cu concentration was significantly altered in response to both age- and AD-related effects, whereas the blood plasma Cu isotope ratio was only affected by the development of AD. Changes in the Cu isotopic signature of the cerebellum were significantly correlated with the changes observed in blood plasma. The brain stem showed a significant increase in Cu concentration for both young and aged AD transgenic mice compared with healthy controls, whereas the Cu isotopic signature became lighter as a result of age-related changes. In this work, ICP-MS/MS and MC-ICP-MS provided relevant and complementary information on the potential role of Cu in ageing and AD.