ABSTRACT
Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.
Subject(s)
Alzheimer Disease/metabolism , Oxidative Stress , Tyrosine/analogs & derivatives , Aged , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Apolipoproteins E/genetics , Brain/metabolism , Brain/pathology , Disease Progression , Female , Genotype , Guanosine/analogs & derivatives , Guanosine/metabolism , Heterozygote , Humans , Male , Middle Aged , Neurofibrillary Tangles/pathology , Neurons/metabolism , Neurons/pathology , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Tyrosine/metabolismABSTRACT
An abnormal expression of noradrenergic proteins (e.g., tyrosine hydroxylase, norepinephrine transporters) in the locus coeruleus has recently been demonstrated in subjects with major depression and/or victims of suicide. Monoamine oxidase A (MAO-A) is a key enzyme in the catabolism of biogenic amines and is expressed in brain noradrenergic neurons. In this study, the binding of [3H]Ro41-1049 to MAO-A was measured by quantitative autoradiography at multiple levels along the rostral-caudal axis of the noradrenergic locus coeruleus from subjects with major depression and age- and postmortem interval-matched control subjects who were psychiatrically normal. [3H]Ro41-1049 binding to MAO-A was unevenly distributed along the axis of the locus coeruleus, paralleling an uneven number of neuromelanin-containing (noradrenergic) neurons throughout the nucleus. Accordingly, there was a significant correlation between the number of neuromelanin-containing neurons per section and the specific binding of [3H]Ro41-1049 at any particular level of the locus coeruleus in control subjects (r(2)=0.25; p<0.001) and in subjects with major depression (r(2)=0.14; p<0. 001). Moderate levels of [3H]Ro41-1049 binding were observed in regions surrounding the locus coeruleus, including the central gray and the dorsal and median raphe nuclei. No significant differences in [3H]Ro41-1049 binding to MAO-A were observed at any level of the locus coeruleus, or raphe nuclei, comparing subjects with major depression to psychiatrically normal control subjects. These findings demonstrate that the pathophysiology of major depression is not likely to involve abnormalities in MAO-A.
Subject(s)
Biogenic Monoamines/metabolism , Brain Stem/enzymology , Depressive Disorder/metabolism , Monoamine Oxidase/metabolism , Adult , Aged , Brain Stem/pathology , Female , Humans , Locus Coeruleus/enzymology , Locus Coeruleus/pathology , Male , Middle Aged , Monoamine Oxidase Inhibitors/pharmacology , Radioligand Assay , Raphe Nuclei/enzymology , Raphe Nuclei/pathology , Thiazoles/pharmacologyABSTRACT
Levels of carboxyhemoglobin that would ordinarily cause little or no noticeable symptoms or other effects proved fatal in individuals suffering from atherosclerotic coronary artery disease. All such deaths that occurred in the Cuyahoga County during a period of 23 years were studied. The pathophysiologic mechanisms that may be operative in these deaths are discussed. The importance of being aware of this fact, while one determines the cause and manner of such deaths, is stressed.