The relationship between Alzheimer disease (AD) and aging is not currently known. In this study, postmortem frontal-and occipital-pole brain samples were obtained from 16 subjects with AD, 8 age-matched controls, and 5 young controls. These samples were analyzed both for protein oxidation products (carbonyl) and the activities of two enzymes vulnerable to mixed-function oxidation, glutamine synthetase and creatine kinase. Glutamine synthetase is more sensitive to mixed-function oxidation than creatine kinase. Carbonyl content rises exponentially with age, at double the rate in the frontal pole compared with the occipital pole. Compared with young controls, both aged groups (AD and age-matched controls) have increased carbonyl content and decreased glutamine synthetase and creatine kinase activities, which are more marked in the frontal than occipital pole in all instances. We conclude that protein oxidation products accumulate in the brain and that oxidation-vulnerable enzyme activities decrease with aging in the same regional pattern (frontal more affected than occipital). However, only glutamine synthetase activity distinguishes AD from age-matched controls: Because glutamine synthetase activity is differentially reduced in the frontal pole in AD, we suggest that AD may represent a specific brain vulnerability to age-related oxidation.Aging can be defined as the nonfunctional alteration of structure or homeostatic capability in an individual organism as it lives (1). A particular consequence of the aging process, at the cellular level, is the accumulation of proteins covalently modified by specific mechanisms-e.g., mixedfunction oxidation (MFO), deamidation, ubiquitin conjugation, and glycation (2-7). These steps have been reported to mark proteins for subsequent proteolysis.MFO is of particular interest because of the site-specific nature of the modifications (8-13), tending to occur near the metal-containing catalytic site of particular enzymes-e.g., glutamine synthetase. Free-radical-mediated forms of MFO could be one of the important mechanisms in normal aging (14)(15)(16), causing protein structural alterations, loss of enzymatic function, or interference with regulatory protein interactions.In this study, we provide evidence that the level of oxidatively modified protein is increased in the aging brain. We also demonstrate that in Alzheimer disease (AD), a disease strongly associated with aging, there is regional loss of glutamine synthetase activity. Glutamine synthetase is an enzyme particularly sensitive to MFO. We propose the hypothesis that AD is an alteration in the normal aging process in selectively vulnerable brain cells or brain areas that are challenged by increased oxidation with advancing age.
MATERIALS AND METHODSBrain Tissue Samples. Brain specimens were obtained at autopsy from 16 patients with AD, 8 age-matched controls (AC), and 5 young controls (YC). Tissues were received from the Kentucky Medical Examiners Program and the University of Kentucky AD Research Center, under approv...