ABSTRACT
Ceruloplasmin (CP), the major plasma anti-oxidant and copper transport protein, is synthesized in several tissues, including the brain. We compared regional brain concentrations of CP and copper between subjects with Alzheimer's disease (AD, n = 12), Parkinson's disease (PD, n = 14), Huntington's disease (HD, n = 11), progressive supranuclear palsy (PSP, n = 11), young adult normal controls (YC, n = 6) and elderly normal controls (EC, n = 7). Mean CP concentrations were significantly increased vs. EC (P < 0.05) in AD hippocampus, entorhinal cortex, frontal cortex, and putamen. PD hippocampus, frontal, temporal, and parietal cortices, and HD hippocampus, parietal cortex, and substantia nigra. Immunocytochemical staining for CP in AD hippocampus revealed marked staining within neurons, astrocytes, and neuritic plaques. Increased CP concentrations in brain in these disorders may indicate a localized acute phase-type response and/or a compensatory increase to oxidative stress.
Subject(s)
Alzheimer Disease/physiopathology , Brain/physiology , Ceruloplasmin/metabolism , Copper/metabolism , Nerve Degeneration/physiology , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Brain/metabolism , Brain/pathology , Case-Control Studies , Cell Count , Hippocampus/pathology , Humans , Huntington Disease/metabolism , Huntington Disease/pathology , Huntington Disease/physiopathology , Middle Aged , Neurons/pathology , Parkinson Disease/metabolism , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Supranuclear Palsy, Progressive/metabolism , Supranuclear Palsy, Progressive/pathology , Supranuclear Palsy, Progressive/physiopathologyABSTRACT
Oxidant-mediated damage is suspected to be involved in the pathogenesis of several neurodegenerative disorders. Iron promotes conversion of hydrogen peroxide to hydroxyl radical and, thus, may contribute to oxidant stress. We measured iron and its transport protein transferrin in caudate, putamen, globus pallidus, substantia nigra, and frontal cortex of subjects with Alzheimer's disease (n = 14) and Parkinson's disease (n = 14), and in younger adult (n = 8) and elderly (n = 8) normal controls. Although there were no differences between control groups with regard to concentrations of iron and transferrin, iron was significantly increased (p < 0.05) in Alzheimer's disease globus pallidus and frontal cortex and Parkinson's disease globus pallidus, and transferrin was significantly increased in Alzheimer's disease frontal cortex, compared with elderly controls. The transferrin/iron ratio, a measure of iron mobilization capacity, was decreased in globus pallidus and caudate in both disorders. Regional transferrin and iron concentrations were generally more highly correlated (Pearson's correlation coefficient) in elderly controls than in Alzheimer's and Parkinson's disease. The altered relationship between iron and transferrin provides further evidence that a disturbance in iron metabolism may be involved in both disorders.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Iron/metabolism , Parkinson Disease/metabolism , Transferrin/metabolism , Adult , Aged , Aged, 80 and over , Cadaver , Female , Humans , Male , Middle Aged , Osmolar Concentration , Reference ValuesABSTRACT
BACKGROUND: An expanded CAG trinucleotide repeat is the genetic trigger of neuronal degeneration in Huntington's disease (HD), but its mode of action has yet to be discovered. The sequence of the HD gene places the CAG repeat near the 5' end in a region where it may be translated as a variable polyglutamine segment in the protein product, huntingtin. MATERIALS AND METHODS: Antisera directed at amino acid stretches predicted by the DNA sequence upstream and downstream of the CAG repeat were used in Western blot and immunohistochemical analyses to examine huntingtin expression from the normal and the HD allele in lymphoblastoid cells and postmortem brain tissue. RESULTS: CAG repeat segments of both normal and expanded HD alleles are indeed translated, as part of a discrete approximately 350-kD protein that is found primarily in the cytosol. The difference in the length of the N-terminal polyglutamine segment is sufficient to distinguish normal and HD huntingtin in a Western blot assay. CONCLUSIONS: The HD mutation does not eliminate expression of the HD gene but instead produces an altered protein with an expanded polyglutamine stretch near the N terminus. Thus, HD pathogenesis is probably triggered by an effect at the level of huntingtin protein.
Subject(s)
Huntington Disease/genetics , Repetitive Sequences, Nucleic Acid/genetics , Alleles , Amino Acid Sequence , Antibodies , Brain/immunology , Brain/pathology , Humans , Huntington Disease/immunology , Immunohistochemistry , Molecular Sequence Data , Peptides/chemical synthesis , Peptides/immunology , Polymorphism, Genetic , Repetitive Sequences, Nucleic Acid/immunology , Tumor Cells, CulturedABSTRACT
CAG repeat expansion in the Huntington's disease gene (HD) was examined in postmortem brains from 310 clinically diagnosed and 15 'at risk' individuals. Presence of an expanded CAG allele (>37 units) was the cause of the disorder in almost all cases (307 of 310). Despite a diversity of reporting clinicians, neurological and psychiatric onset and age at death all displayed significant inverse correlations with CAG number indicating that diagnosis of onset is reasonably accurate, and that most patients die from the disease and its complications. Neuronal changes before clinical onset are not detected by conventional microscopic examination as three out of 15 'at risk' brains had an expanded CAG allele but no neuropathology. The cause of HD-like neuropathology in three exceptional brains from clinically diagnosed individuals is unclear. The disorder in these cases could be an HD phenocopy or result from alternative mutational mechanisms at the HD locus.
