Towards a Unified Vision of Copper Involvement in Alzheimer's Disease: A Review Connecting Basic, Experimental, and Clinical Research

Abstract

Copper is an essential micronutrient for physiological cell functioning and central nervous system (CNS) development. Indeed, it is a cofactor of many proteins and enzymes in a number of molecular pathways, including energy generation, oxygen transportation, hematopoiesis, cellular growth and metabolism, and signal transduction. This is because it serves as a catalyst of reduction-oxidation (redox) reactions in these processes. When copper is kept under control, bound to special proteins, it yields key properties. However, when it spirals out of control, it is exchanged among small compounds (it is loosely bound to them), and its redox activity makes it dangerous for cell viability, promoting oxidative stress. Copper homeostasis in the CNS is securely synchronized, and perturbations in brain copper levels are known to underlie the pathoetiology of wide spectrum of common neurodegenerative disorders, including Alzheimer's disease. The main objective of this review is to provide some of the most relevant evidence gleaned from recent studies conducted on animal models and humans, and to discuss the evidence as it pertains to a new concept: Aberrant copper metabolism, which appears to have a genetic basis, is a modifiable risk factor accelerating Alzheimer's disease and initiation/progression of cognitive deficits in a percentage of susceptible persons.

Sodium selenate regulates the brain ionome in a transgenic mouse model of Alzheimer’s disease

“…Almost all examined elements (12 out of 15) were considered as DCEs at one or more time points (p < 0.05, Table 1), which was also supported by repeated-measures analysis of variance (ANOVA). The majority of them appeared to be significantly enriched in the brain tissues of 3×Tg-AD mice for a relatively long period, including Fe, Zn, Cu, cadmium (Cd), mercury (Hg) and bismuth (Bi) whose levels in the brain have been reported to be elevated in AD383940414243444546. Excess Fe has been linked to the development of AD, which may combine with Aβ in the APs to accelerate neuronal Aβ production and cognitive impairment39.…”

“…Zn is an essential trace element for the brain development and its proper functions, whose misbalance is thought to be involved in the pathogenesis of AD40. In addition, aberrant Cu metabolism is also a potential risk factor accelerating AD41. Higher Hg concentrations were found in brain regions and blood of some patients with AD42.…”

Texture analyses of quantitative susceptibility maps to differentiate Alzheimer's disease from cognitive normal and mild cognitive impairment

“…For instance, increased levels of copper and altered copper homeostasis contribute to AD by promoting beta-amyloid secretions. 24,25 Dysregulation of neuronal zinc homeostasis also plays a key role in AD (Ref. 26) by inducing parenchymal and cerebrovascular amyloids in transgenic mice.…”

Mortality for chronic-degenerative diseases in Tuscany: Ecological study comparing neighboring areas with substantial differences in environmental pollution

“…Similar evidences have been reported also for other metals, largely released in the area of the study. An altered cerebral zinc homeostasis is associated with generation of extracellular β-amyloid plaques and neuronal neurofibrillary tangles [31], while an increase in non-ceruloplasmin-bound copper has been reported both in animal models and in humans affected by Alzheimer disease [32]. Finally, both groundwater arsenic levels and chronic low-level cumulative exposure to lead (as assessed by bone lead content) appears to be associated with cognitive decline humans [33,34].…”