Redox balance in AD

A premier feature of normal aging and neurodegeneration in the brain is the presence of oxidative stress. This is defined as a disturbance in the pro-oxidant-antioxidant balance in favor of the pro-oxidant, leading to potential oxidative damage. As a principal source of oxidizing radicals, immune cells have attracted longstanding interest in our lab. The 'killing' action of microglia (and other macrophages in the body) comes in part from superoxide anion production by the respiratory burst NADPH oxidase, dismutation of superoxide by superoxide dismutase (discovered by Dr. Erwin Fridovich, Department of Biochemistry, Duke University) to hydrogen peroxide, and the eventual production of toxic oxygen radicals. Such highly reactive chemical species kill bacteria and other invaders by oxidizing proteins, DNA and lipids. Thus, microglia can be viewed as the "bombardier beetle" of the brain.

Oxidation also affects normal cell processes in the brain. In studies done at the NIH and at Georgetown University Medical School, Dr. Colton in collaboration with Dr. Daniel Gilbert, found that synaptic transmission was particularly susceptible to oxygen such that excess oxygen dramatically increased the spontaneous release of a key excitatory neurotransmitter, glutamate, while oxidizing and inactivating key enzymes such as the Na-K ATPase and glutamic acid decarboxylase. These changes remain likely explanations for the seizure-promoting action of hyperbaric oxygen in mammals. Oxygen radicals such as hydrogen peroxide or hydroxyl depress synaptic transmission and block long term potentiation (LTP) in mammalian hippocampus. These initial studies led to the discovery of a redox site on the NMDA channel that decreases NMDA channel ionic current when oxidized and increases it when reduced.

Disruptions in anti-oxidant protection occur in AD and other neurodegenerative diseases such as Down syndrome. Interestingly, one of the principal anti-oxidants of the brain is nitric oxide (NO), which blocks superoxide-mediated damage to membrane lipids. This is extremely important to the nervous system because brain cells contain high levels of polyunsaturated fatty acids (PUFAs) that can be easily oxidized and thus damaged. NO, however, mediates a variety of physiological processes ranging from regulation of vascular tone to cell proliferation to neuronal function. The complex biochemistry of NO has been elegantly described by a close colleague of the lab, Dr. David Wink of the NCI, NIH.

NO's interaction with iron-containing proteins leads to the "direct" effects of NO that are epitomized by activation of quanyl cyclase to make cyclic GMP. These reactions occur at low nanomolar concentrations of NO and regulate normal physiology. At intermediate levels, NO regulates cell survival and protection mechanisms. At the highest levels of NO, however, a different scenario unfolds. Reactive oxygen nitrogen species (RNOS) are formed, leading to multiple reactions that can be oxidizing (through interaction with superoxide anion) or nitrosative (via nitration or nitrosation). These high (10uM) levels of NO are easily seen in tissue culture stimulation of rodent macrophages or in severe acute illness. NO under these conditions is made by the inducible nitric oxide synthase (iNOS) found in macrophages and in other cell types including neurons.

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