Role of zinc and copper ions in the pathogenetic mechanisms of traumatic brain injury and Alzheimer’s disease

Abstract

The disruption of homeostasis of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Wilson’s, Creutzfeldt-Jakob, Parkinson’s, and Alzheimer’s diseases (AD), and traumatic brain injury (TBI). The last two pathological conditions of the brain are the most common; moreover, it is possible that TBI is a risk factor for the development of AD. Disruptions of Zn2+ and Cu2+ homeostasis play an important role in the mechanisms of pathogenesis of both TBI and AD. This review attempts to summarize and systematize the currently available research data on this issue. The neurocytotoxicity of Cu2+ and Zn2+, the synergism of the toxic effect of calcium and Zn2+ ions on the mitochondria of neurons, and the interaction of Zn2+ and Cu2+ with β-amyloid (Abeta) and tau protein are considered.

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter

“…With this in mind, the SLC30A9 coevolution with the mitochondrial oxidative phosphorylation chain components is informative. However, excess zinc has adverse impacts on the mitochondrial respiratory chain and has been implicated in several pathologies including Alzheimer’s disease and stroke (Cherny et al, 2001; Granzotto et al, 2020; Isaev et al, 2020; Lee et al, 2012; Nolte et al, 2004; Pan et al, 2015; Sensi et al, 2009; Wang et al, 2010; Yin et al, 2019; Zhao et al, 2018). Importantly, a mechanism of zinc efflux from the mitochondria had, heretofore, not been identified.…”

“…This is especially the case for mitochondrial zinc, which, as a cofactor of several mitochondrial enzymes, is a critical component of mitochondrial physiology (Granzotto et al, 2020;Ji et al, 2020;Turan and Tuncay, 2021). In parallel to full-cell consequences of zinc dysregulation, mitochondrial zinc overload is toxic and has been linked to traumatic brain injury and stroke (Frederickson et al, 2004;Galasso and Dyck, 2007;Granzotto et al, 2020;Isaev et al, 2020;Ji et al, 2019;Nolte et al, 2004;Pan et al, 2015;Qi et al, 2019;Sensi et al, 2011Sensi et al, , 2009Yin et al, 2019;Zhao et al, 2018). The mechanisms of mitochondrial zinc regulation are poorly understood and neither SLC30A nor SLC39A members have been directly shown to localize in the mitochondria.…”

Zinc and Traumatic Brain Injury: From Chelation to Supplementation

“…For example, it has been hypothesized that release of zinc from MT-3 after injury induces reactive oxygen species [20]. The resulting oxidative stress then leads to a cascade of secondary injury mechanisms such as mitochondrial disruption and inflammation [21]. Other mechanisms that appear to be involved include zinc-induced NAD + deficiency that impairs glycolysis [22,23], activation of the nerve growth factor receptor TrkA [24], zinc-mediated mitochondrial dysfunction [25], and poly(ADP-ribose) polymerase (PARP) activation [26].…”

Zinc Binding to NAP-Type Neuroprotective Peptides: Nuclear Magnetic Resonance Studies and Molecular Modeling

“…Thus, it was observed that high concentrations of zinc coincide with the regions where amyloid plaques form according to the post-mortem investigation of AD patients [13]. Therefore, the induction of Aβ oligomerization is considered as the main contribution of zinc ions to the pathogenesis of AD [14,15]. Furthermore, different fragments derived from activity-dependent neuroprotective protein (ADNP) have been studied as potential anti-AD drugs [15,16].…”

“…Therefore, the induction of Aβ oligomerization is considered as the main contribution of zinc ions to the pathogenesis of AD [14,15]. Furthermore, different fragments derived from activity-dependent neuroprotective protein (ADNP) have been studied as potential anti-AD drugs [15,16]. For instance, the neuroprotective 1 NAPVSIPQ 8 peptide (NAP) contains two prolines, which confer β conformation.…”