ReviewOxidative stress in Alzheimer's disease
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 = Aβ
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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