An unconventional hypothesis of oxidation in Alzheimer's disease: intersections with excitotoxicity.
There are two major lines of investigation from which a connection has been traditionally drawn between chemical oxidation and Alzheimer's disease. First, a major risk factor for AD is age, and oxidative stress has long been a component of general hypotheses about biological aging. The second line of reasoning is a corollary of the Amyloid Hypothesis, the assumption that the amyloid beta-peptide (A-beta) which comprises AD's pathognomic plaques is a key mediator of the neurodegeneration occurring in this disorder. Under many experimental conditions, A-beta has been shown to evoke oxidative damage to tissues, cells, and biomolecules; even the redox properties of the peptide itself have been hotly debated. These two modalities of conjecture intersect under the Inflammatory Hypothesis of AD, as inflammation produces oxidation, old age is associated with elevation in inflammatory events, and A-beta can further exacerbate such inflammatory reactions in brain cells. This review discusses these arguments about the pathogenesis of AD and how they might be generalized to other neurodegenerative conditions. But, additional speculation is offered in the form of an inclusionary mechanism that may be specific and novel enough to qualify as a third line of theory; namely, the possibility that inflammatory reactions in microglia--activated by A-beta or other factors among the "usual suspects"--initiate programmed oxidation that is converted to the neuron-specific stress of excitotoxicity.
Barger
Steven W
SW
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock AR 72205, USA. sbarger@uams.edu
D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000473:pathology; D003553:Cystine / Q000737:chemistry; D005971:Glutamates / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D019998:Racemases and Epimerases / Q000737:chemistry; D016897:Respiratory Burst; D012307:Risk Factors; D012694:Serine / Q000737:chemistry; D000099300:Serine Racemase
D016229:Amyloid beta-Peptides; D003553:Cystine; D005971:Glutamates; D010100:Oxygen; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase