Abstract
The biological transition metals iron (Fe), copper (Cu) and zinc (Zn) are thought to contribute to the neuronal pathologies that occur following traumatic brain injury (TBI), and indeed our previously published work in young (3 month-old) mice clearly demonstrates a significant spatiotemporal modulation of metals following TBI. Of note, however, is the literature observation that there is both an apparent detrimental effect of aging on TBI outcomes and an alteration in metals and their various transporters with normal advancing age. Therefore, to determine whether there was an interaction between aging, metals and TBI, we have utilised laser ablation-inductively coupled plasma-mass spectrometry to examine the spatial and temporal distribution of Fe, Zn and Cu following an acute controlled cortical impact brain injury in aged (24 months) rodents. The relative abundance of metals in corresponding regions within the ipsilateral and contralateral hemispheres as well as the hippocampus was assessed. Substantial region and time point specific alterations in Fe, Zn and Cu were identified immediately and up to 28 days post-TBI. The data from this follow-up study has also been compared to our previous data from young animals, and aged mice exhibit an appreciably enhanced and persistent elevation of all metals in every region surveyed, with individual metal disparities at various time points observed post-injury. This may potentially contribute to the acceleration in the onset of cognitive decline and neurological disease that has been observed in the aged population following head trauma.
Highlights
Metals play critical roles in brain health
These observations have led to the metal dyshomeostasis theory, which implicates metals in the cellular cascades that contribute to Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and other conditions.[26,27]
A comparison of ipsilateral to contralateral hemispheres revealed that, after traumatic brain injury (TBI), the Fe levels were significantly increased within the immediate vicinity of the impact site (ROI1 p o 0.0001; Fig. 3a) and in the two additional regions of interest (ROIs) extending radially from the lesion site (ROI2 p o 0.0001; ROI3 p o 0.01; Fig. 3b and c) leading to a significant overall increase in iron over the entire ipsilateral hemisphere (p o 0.001; Fig. 3d)
Summary
The spatial changes we have observed in the levels of iron, zinc and copper in the aged brain, both in naıve and brain injured animals, highlight the potential interaction of these metals in both age- and injury-related functional deficits. This suggests the use of metal-targeted therapeutics could be used to improve outcomes post-injury. Fe storage increases with age in the human brain in the cortex, hippocampus and basal ganglia, and the main cell types shown to accumulate Fe are microglia and astrocytes.[28] The labile iron pool can increase to potentially harmful levels whereby elevated and unregulated reactive oxygen species (ROS) can lead to oxidative damage and cell death. Adequate concentrations of Zn are required for normal neurotransmission, and synaptic vesicular Zn is required for normal memory function,[31] and the Zn transporter responsible for loading presynaptic vesicles with Zn (ZnT3) has been shown to decrease with age in both rodents and humans.[31]
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