Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

Abstract

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

A Metallo Pro‐Drug to Target CuII in the Context of Alzheimer's Disease

“…[2a, 3] In Alzheimer's disease (AD), copper ions bound to extracellular amyloid-β (Aβ) peptide produce ROS and contribute to the oxidative stress observed in the disease. [3] It has indeed been shown that the Cu(Aβ) species can catalyse the incomplete reduction of dioxygen leading to O 2 •- , H 2 O 2 and HO • . [4] In living organisms, efficient pathways to finely tune the concentrations in O 2 ◦- and H 2 O 2 have evolved to protect endogenous components against oxidative damage and to control the ROS concentrations to appropriate levels.…”

“…[15] In the present communication, we used complex 1 + instead of following a classical chelating strategy [16] and using a free ligand that might be toxic. Furthermore in the context of AD, the importance of oxidative stress is widely acknowledged, [3] proving relevant the use of a SOD mimict. We will thus describe here how compound 1 + , which has an interesting intrinsic SOD-like ability, prevents Cu-induced processes by removing Cu(II) from Aβ, that is to say how it prevents ROS production and alteration of Aβ aggregation.…”

“…Asc oxidation is directly associated to the production of ROS, since it is the (physiological) reductant required to fuel the reduction of dioxygen to O 2 •- , H 2 O 2 and HO • . [3] In addition, release of HO • by the Cu(Aβ)/Asc/O 2 catalytic system has been monitored using the 3-CCA fluorescence assay (Figure S11). [26] Results parallel those obtained in the Asc consumption test indicating the prevention of HO • release when 1 + is added to the mixture This important observation indicates that both 1 + and LH are thermodynamically and kinetically competent for the swapping and removal of Cu(II) bound to Aβ.…”

Oxidative Stress: Noxious but Also Vital

“…The maintenance of cell redox state is important to cell viability [43]. The increased level of reactive species can lead to oxidative damage to a vast number of biological molecules, as DNA [44][45][46], proteins [47], lipids [48], including membranes [3] leading to a range of pathologies, as cancer [36], neurological disease [49], cardiac disease [50,51], inflammation process [52] and aging.…”

Crystal structure of catena-poly[[[dichloridocopper(II)]-{μ-tert-butyl N-methyl-N-[4-(6-{[4-(pyridin-2-yl-κN)-1H-1,2,3-triazol-1-yl-κN 3]methyl}-1,3-benzothiazol-2-yl)phenyl]carbamato}] acetonitrile monosolvate]

“…Alzheimer's Disease (AD) is a neurodegenerative disease characterized by aggregation of amyloid peptide and extensive inflammation related to a strong oxidative stress (Cheignon et al, 2018). Metals are known to play a key role in this oxidative stress and also to be associated with peptide aggregation, at the core of the pathology (Faller et al, 2013;Viles, 2012).…”