Oxidative alterations in Alzheimer's disease.
There is increasing evidence that free radical damage to brain lipids, carbohydrates, proteins, and DNA is involved in neuron death in neurodegenerative disorders. The largest number of studies have been performed in Alzheimer's disease (AD) where there is considerable support for the oxidative stress hypothesis in the pathogenesis of neuron degeneration. In autopsied brain there is an increase in lipid peroxidation, a decline in polyunsaturated fatty acids (PUFA) and an increase in 4-hydroxynonenal (HNE), a neurotoxic aldehyde product of PUFA oxidation. Increased protein oxidation and a marked decline in oxidative-sensitive enzymes, glutamine synthetase and creatinine kinase, are found in the brain in AD. Increased DNA oxidation, especially 8-hydroxy-2'-deoxyguanosine (8-OHdG) is present in the brain in AD. Immunohistochemical studies show the presence of oxidative stress products in neurofibrillary tangles and senile plaques in AD. Markers of lipid peroxidation (HNE, isoprostanes) and DNA (8-OHdG) are increased in CSF in AD. In addition, inflammatory response markers (the complement cascade, cytokines, acute phase reactants and proteases) are present in the brain in AD. These findings, coupled with epidemiologic studies showing that anti-inflammatory agents slow the progression or delay the onset of AD, suggest that inflammation plays a role in AD. Overall these studies indicate that oxidative stress and the inflammatory cascade, working in concert, are important in the pathogenetic cascade of neurodegeneration in AD, suggesting that therapeutic efforts aimed at both of these mechanisms may be beneficial.
Markesbery
W R
WR
Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, Department of Pathology, University of Kentucky Medical Center, Lexington, USA. wmarkesbery@aging.coa.uky.edu
Carney
J M
JM
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007501:Iron / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D011506:Proteins / Q000378:metabolism