ROLE OF METAL IONS IN NEURODEGENERATION: INVESTIGATING THE CHEMISTRY OF COPPER, IRON, AND ZINC IN ALZHEIMER'S AND PARKINSON'S DISEASES

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD), well-known neurodegenerative disorders, are related to the progressive loss of neuronal functions and to the accumulation of pathologically aggressive proteins. Recent evidence has shown that metal ions play an important role in the pathogenesis of these disorders, involving metal ions like copper (Cu), iron (Fe), and zinc (Zn). These ions create oxidative stress, induce protein aggregation, and invoke neurotoxicity, furthering the progression of these diseases. On one hand, Cu and Fe take part in free radical generation through redox reactions, while on the other, they induce oxidative damage; Zn, however, acts in a manner to alter protein interactions and aggregation. An imbalance of these metal ions has been observed in postmortem brain specimens from AD and PD subjects, implicating these metal ions in disease etiology.

The perturbation of metal homeostasis means an alteration not only in oxidative stress but also in other pivotal biological pathways, including mitochondrial dysfunction, synaptic signaling, and neuroinflammation. Increased accumulation of Fe in the PD patient substantia nigra and of Cu in the AD patient amyloid plaques underlines their pathological significance. Moreover, Zn has also been implicated in modulating amyloid-beta (Aβ) aggregation, playing either a protective role or detrimental role depending on its level of availability and binding state.

Herein, we investigate the chemistry of Cu, Fe, and Zn in the context of neurodegeneration, their involvement in oxidative stress, and also some potential therapeutic interventions such as chelation and ionophores to alleviate their detrimental effects. With a complete knowledge of metal ions-neurodegeneration interactions, new therapeutic approaches can be developed to target metal-induced toxicity and restore neuronal homeostasis.