Elsevier

Pathophysiology

Volume 13, Issue 3, August 2006, Pages 195-208
Pathophysiology

Review
Oxidative stress in Alzheimer's disease

https://doi.org/10.1016/j.pathophys.2006.05.004Get rights and content

Abstract

Oxidative damage is a major feature in the pathophysiology of Alzheimer's disease (AD). In this review, we discuss free radical-mediated damage to the biochemical components involved in the pathology and clinical symptoms of AD. We explain how amyloid beta-protein (Aβ), microtubule-associated protein tau, presenilins, apolipoprotein E, mitochondria and proteases play a role in increasing oxidative stress in AD. Aβ not only can induce oxidative stress, but its generation is also increased as a result of oxidative stress. Finally, a hypothetical model linking oxidative stress with beta-amyloid and neurofibrillary tangle pathology in AD is proposed.

Section snippets

Alzheimer's disease and its pathology

Alzheimer's disease (AD) affects an estimated 25 million people worldwide. AD is characterized by neuronal cell loss and by progressive accumulation of paired helical filaments (PHF) as neurofibrillary tangles (NFT) in neurons, and of amyloid fibers in neuritic (senile) plaques and in the walls of blood vessels [1], [2]. The major amyloid protein in AD and also in adult Down syndrome (DS) is amyloid beta-protein (Aβ) of 39–43 amino acids [3]. Aβ exists in both soluble and fibrillar forms.

AD and oxidative stress

Oxidative stress, in general, is the overpowering of the antioxidative defense system by the oxidative system, as shown in Fig. 1 for Alzheimer's disease. Oxidative stress is produced by free radicals, i.e. reactive oxygen species (ROS) that are generated by oxygen- and nitrogen-based molecules that have unpaired electrons. The general mechanism of free radical generation is shown in Fig. 2. Because of unpaired electrons, free radicals are very unstable and highly reactive. In order to make

Oxidation, phospholipid asymmetry, Aβ and its aggregation

We have previously reported that acidic lipids such as phosphatidylserine (PS), cardiolipin (CL), phosphatidic acid (PA), phosphatidylinositol (PI), PI 4-phosphate, and PI 4,5-bisphosphate can promote the fibrillization of amyloid beta-protein [141]. Aβ was found to increase the fluorescence of 1-acyl-2-[12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-glycero-3-phosphate (NBD-PA) in a concentration-dependent manner. The order of interaction of Aβ peptides with NBD-PA was Aβ 1-43 = 

Antioxidant therapy in AD

Oxidative stress in AD is compounded by many factors such as aging, amyloid plaques, and NFT pathology, as shown in Fig. 1, Fig. 3. Although it is apparent that free radical-mediated assault on lipids, proteins, and nucleic acids results in oxidative stress, these free radicals can easily be scavenged by dietary means. Naturally occurring compounds with antioxidant capacity are available and widely marketed (e.g. Vitamin E, Vitamin C, ubiquinone, lipoic acid, beta-carotene, melatonin,

Concluding remarks

Oxidative stress plays an important role in the development and progression of AD pathology. Extensive evidence suggests ROS-mediated oxidative damage to proteins, lipids and nucleic acids in AD. Aβ fibrillization is a key event in the amyloid plaque formation in AD. However, a precise sequence of events leading to Aβ fibril formation is not well understood. Based on Aβ and oxidative stress-dependent externalization of PS, and interaction of Aβ with acidic lipids, a hypothetical model linking

Acknowledgements

This work was supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities, and by NIH Grant No. AG020992.

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