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.

Wilson Disease: Intersecting DNA Methylation and Histone Acetylation Regulation of Gene Expression in a Mouse Model of Hepatic Copper Accumulation

“…38 Interestingly, Parkinson's and Alzheimer's diseases have been associated with both high and low copper levels in the brain. 39,40 Corroborating our studies, increased histone acetylation was associated with reduced HDAC levels in mouse brains as well as midbrain tissues of patients with Parkinson's disease. 41 Previous studies have shown a role for class IIa HDACs in gene expression regulation of cardiac hypertrophy and contractile dysfunction.…”

Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration

“…Some studies reported the potential role of Aβ monomers as antioxidants, depending on the metal ion concentration in vitro [ 49 , 50 ]. In contrast, other studies showed that oligomeric Aβ, the dominant form in patients with AD, promotes ROS production in cooperation with metal ions in vitro and in vivo [ 51 , 52 , 53 , 54 ]. In addition, inhibition of the γ-secretase activity was reported to reduce the levels of ROS and oxidize proteins, and to enhance resistance to oxidative stress [ 55 ].…”

Nasal Delivery of D-Penicillamine Hydrogel Upregulates a Disintegrin and Metalloprotease 10 Expression via Melatonin Receptor 1 in Alzheimer’s Disease Models

“…Major pathological hallmarks of AD are senile plaques (SPs), composed of self-polymerized amyloid-β peptide (Aβ), and neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins (Selkoe, 1991;Hardy and Higgins, 1992). In accordance with the metal hypothesis of AD, Aβ deposition, and tau hyperphosphorylation are aggravated by metal ions, thus promoting the development of AD (Liu et al, 2011;Zhang et al, 2019;Ejaz et al, 2020;Singh et al, 2020;Spotorno et al, 2020). The "metal hypothesis" describes the unbalanced theory of the level and location of metal ions in the pathogenesis of AD (Yang et al, 2019;Patel and Aschner, 2021).…”