Copper Toxicity Links to Pathogenesis of Alzheimer's Disease and Therapeutics Approaches

Abstract

Alzheimer's disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals' roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions' current status in several AD features, and some conflicting reports are present herein.

Keywords: Alzheimer’s disease; amyloid plaques; copper; neurodegeneration; oxidative damages; protein modification.

Figure 1

Copper’s role in the aggregation of Aβ peptides in the neuritic plaques of AD. (A) Cu²⁺ complexes with beta-amyloid peptides lead to dityrosine-linked β-amyloid dimer formation, which is neurotoxic and resists degradation into monomers. (B) Cu binding with the Y10A mutant peptide causes no neurotoxicity, dityrosine cross-linking, and degrades to monomers via degrading agents

Figure 2

Dysfunction of autophagy and tau protein neurofibrillary tangles (NFTs) in the hippocampus of AD. Oligomeric Aβ-induced ROS production results in oxidative damage and mitochondrial dysfunction, in which hyperphosphorylated tau protein and NFTs produce through an imbalance of various protein kinases and phosphatases. These events lead to autophagic dysfunction and aggregated tau protein to neuronal loss in Alzheimer’s disease.

Figure 3

Redox cycling of Cu²⁺/Cu⁺ with Aβ peptides leads to the production of hydrogen peroxide. Unstable reactive oxygen species (ROS) production from H₂O₂ results in oxidative stress, leading to mitochondrial dysfunction, oxidative cellular damage, and neuronal loss. Cytotoxic end-products of lipid peroxidation malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) promote cell death.

Figure 4

Schematic representation of the effects and correlation between Cu and cholesterol-rich lipid rafts in Alzheimer’s disease. (A) The enzymes that are present in lipid rafts are responsible for the cleavage of APP to Aβ peptide. (B) Cu deficient AD brains lead to copper accumulation in lipid rafts, and rising concentrations of Cu results in higher Aβ production due to an increase in β-secretase activity. (C) Calcium-permeable pores formed by small oligomers of Aβ peptides. These pores are calcium channels and disrupt cellular Ca²⁺ homeostasis, eventually leading to neuronal death.

Figure 5

Multifunctional compounds (MFCs) target for Alzheimer’s Disease.

Figure 6

Structure of bifunctional chelating agents from various research groups’ reports as discussed in the text.