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

Hafza Wajeeha Ejaz,Minglin Lang,Wei Wang

doi:10.3390/ijms21207660

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.

Highlights

Alzheimer’s disease (AD) is a multifactorial, complex brain disease defined by progressive cognitive decline, heterogeneity of behavioral presentations, and dementia in older people [1,2,3]
Cu is absorbed through a high-affinity copper transporter Ctr1, incorporating cuprous (Cu+) ions from the intestinal microvilli’s surface
Little is known about Cu2+ absorption, which is probably absorbed by divalent metal transporter 1 (DMT1) or other shared metal transporters [218]

Summary

Introduction

Alzheimer’s disease (AD) is a multifactorial, complex brain disease defined by progressive cognitive decline, heterogeneity of behavioral presentations, and dementia in older people [1,2,3]. In 1907, Alois Alzheimer was the first to identify a mental decline with amyloid plaques and neurofibrillary tangles found in most dementia symptoms [4,5]. This disorder’s main risk factor is old age, because the elderly are more prone to diseases, affecting 10% of people aged 65, and this proportion rises by about three times for people aged 85 and older [6,7]. AD typically destroys neurons, and their connection with the brain regions such as the entorhinal cortex and hippocampus area, the parts of the brain essential in forming memories [8]. It is one of the leading causes of death [11] that we are currently unable to stop or cure because the underlying etiology is poorly understood at present [11,12]

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