Environmental and Dietary Exposure to Copper and Its Cellular Mechanisms Linking to Alzheimer’s Disease

Abstract

Metals are commonly found in the environment, household, and workplaces in various forms, and a significant segment of the population is routinely exposed to the trace amount of metals from variety of sources. Exposure to metals, such as aluminum, lead, iron, and copper, from environment has long been debated as a potential environmental risk factor for Alzheimer's disease (AD) for decades, yet results from in vitro, in vivo, and human population remain controversial. In the case of copper, the neurotoxic mechanism of action was classically viewed as its strong affinity to amyloid-beta (Aβ) to help its aggregation and increase oxidative stress via Fenton reaction. Thus, it has been thought that accumulation of copper mediates neurotoxicity, and removing it from the brain prevents or reverse Aβ plaque burden. Recent evidence, however, suggests dyshomeostasis of copper and its valency in the body, instead of the accumulation and interaction with Aβ, are major determinants of its beneficial effects as an essential metal or its neurotoxic counterpart. This notion is also supported by the fact that genetic loss-of-function mutations on copper transporters lead to severe neurological symptoms. Along with its altered distribution, recent studies have also proposed novel mechanisms of copper neurotoxicity mediated by nonneuronal cell lineages in the brain, such as capillary endothelial cells, leading to development of AD neuropathology. This review covers recent findings of multifactorial toxic mechanisms of copper and discusses the risk of environmental exposure as a potential factor in accounting for the variability of AD incidence.

Risk factors for Alzheimer’s disease

“…New risk factors have also been identified including those associated with diet such as obesity [31,71,125,185], diabetes [4,118,124] and factors associated with the immune system [12,128,141,158]. With reference to metal exposure, the case for aluminium is less strong but other metals such as zinc and copper have been implicated, and the interactions among different metals emphasised [16,86,147,156]. Recent data have also increased the probability that exposure to infectious agents could be involved [89].…”

“…Since the 1980s, there has been more general concern regarding metal exposure as the ability of cells to efficiently maintain key processes with age, such as energy production, repair, and regeneration, is dependent on a range of metals [156]. In addition, a significant proportion of the population are routinely exposed to trace metals such as aluminium, lead, iron, and copper, obtained from a variety of sources, and all are potential risk factors for AD [86]. Arsene et al [16], however, reported no relationship between metal accumulation with age or neurodegeneration suggesting the brain was not a favourable site for metal accumulation.…”

“…Regarding the individual metals, more recent studies of aluminium report significantly increased mortality from AD among miners exposed to aluminium-rich dust [147] suggesting that some aspects of this hypothesis might be worth revisiting. In addition to aluminium [195], zinc [127,192], mercury [140], copper [86,144], manganese [45,186], cadmium [136,142], and magnesium [188] have all been suggested as risk factors for AD. Many of these metals have been shown to interact directly with APP metabolism or with APOE [140].…”

Effects of copper‐impregnated collagen implants on local pro‐ and anti‐inflammatory and regenerative tissue reactions following implantation in rats

“…Maintained Cu 2+ exposure is possibly linked to the development of Alzheimer's disease through formation of Cu 2+ -amyloid-beta complex and promotion of a microglial pro-inflammatory M1 phenotype as opposed to an antiinflammatory M2 phenotype associated with Cu + (Hsu, Bondy, & Kitazawa, 2018). First, while it would have been interesting to resolve the disposition and chemical reactions of the acetate ions in vivo including possible changes of pH in the peri-implant tissue, these aspects are difficult to address by experimental methods and beyond the aims of the study.…”

“…It should be kept in mind that the study has a number of limitations. First, while it would have been interesting to resolve the dispo- (Hsu, Bondy, & Kitazawa, 2018). A more general concern regarding a possible use of Cu for impregnation of biomaterials which has to be carefully considered is the risk of accumulation to critical concentrations in the environment similar to other metals like mercury, lead, zinc, or cadmium, causing coselection of antibiotic resistance in bacteria (Imran, Das, & Naik, 2019).…”