8-hydroxyguanosine and Nerve-Degeneration

Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.

Topics: Aldehydes; Alzheimer Disease; Animals; Guanosine; Humans; Mice; Nerve Degeneration; Neurofibrillary Tangles; Oxidative Stress; Phosphorylation; tau Proteins

In an analysis of amyloid pathology in Alzheimer disease, we used an in situ approach to identify amyloid-beta (Abeta) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal-specific antibodies directed against Abeta40 and Abeta42 were used for immunocytochemical analyses, Abeta42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Abeta-oligomer. In comparison to the Abeta42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Abeta42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r=- 0.61, p<0.02). Together with recent evidence that the Abeta peptide can act as an antioxidant, these results suggest that intraneuronal accumulation of non-oligomeric Abeta may be a compensatory response in neurons to oxidative stress in Alzheimer disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cell Nucleus; Cytoplasm; Cytoprotection; Female; Guanosine; Humans; Immunohistochemistry; Male; Nerve Degeneration; Neurons; Nucleic Acids; Oxidative Stress; Peptide Fragments

Dentatorubral-pallidoluysian atrophy (DRPLA) is one of the CAG-repeat diseases, and is classified into juvenile and early adult types showing progressive myoclonus epilepsy (PME) in addition to late adult type. We immunohistochemically examined accumulation of oxidative products and expression of superoxide dismutase (SOD) in autopsy cases of DRPLA. Oxidative products to nucleosides, 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine, were accumulated in the lenticulate nucleus predominantly in DRPLA cases having PME. Neuronal accumulation of 4-hydroxy nonenal, a reactive lipid aldehyde, was found in the hippocampus, globus pallidus and cerebellar dentate nucleus in adult DRPLA cases and controls. Cytoplasmic immunoreactivity for Cu/ZnSOD was reduced in the external segment of globus pallidus, dentate nucleus and cerebellar cortex in DRPLA cases. Mitochondrial immunoreactivity for MnSOD was reduced in the lenticulate nucleus and cerebellum in DRPLA cases having PME. Some DRPLA cases showed reduced immunoreactivity for MnSOD in the cerebral cortex. Coexistence of reduced SOD expression and polyglutamine was observed in a few cases. It has been discussed in Huntington's disease that expanded polyglutamine can lead to oxidative neurodegeneration. It is likely that oxidative stress can be involved in DRPLA, although relationship with expanded polyglutamine remains to be elusive.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aldehydes; Autopsy; Biomarkers; Brain; Cytoplasm; Deoxyguanosine; Female; Guanosine; Humans; Immunohistochemistry; Male; Middle Aged; Mitochondria; Myoclonic Epilepsies, Progressive; Nerve Degeneration; Neurons; Oxidative Stress; Peptides; Superoxide Dismutase

Xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are caused by a genetic defect of nucleotide excision repair mechanisms, showing cutaneous hypersensitivity to sunlight and progressive neurological disturbances. The cause of neurological abnormalities has yet to be clarified and fundamental treatments have never been established in both disorders. In order to investigate neurodegeneration of XPA and CS, we immunohistochemically examined deposition of oxidative stress-related materials of nucleotides and expression of two types of superoxide dismutase (SOD) in the brains from autopsy cases of XPA and CS. Cases of XPA but not CS demonstrated nuclear deposition of 8-hydroxy-2'-deoxyguanosine and cytoplasmic deposition of 8-hydroxyguanosine, being speculated as oxidative stress-related materials of DNA and RNA, respectively, in the globus pallidus. Four of five XPA cases exhibited reduced neuronal immunoreactivity for Cu/ZnSOD in the cerebral and cerebellar corteces in addition to the basal ganglia, and two XPA cases showed reduced immunoreactivity for MnSOD in the brain regions examined. In contrast, five CS cases demonstrated comparatively preserved immunoreactivity for Cu/ZnSOD and MnSOD. Both XPA and CS cases showed increased cytoplasmic immunoreactivity for Cu/ZnSOD and/or MnSOD in the microglial cells in the cerebral and cerebellar white matters. These findings suggest that oxidative damage to nucleotides and disturbed SOD expression can be involved in neurodegeneration in XPA but not CS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Biomarkers; Brain; Child; Cockayne Syndrome; Deoxyguanosine; DNA Damage; Down-Regulation; Female; Guanosine; Humans; Immunohistochemistry; Male; Microglia; Nerve Degeneration; Nucleotides; Oxidative Stress; Superoxide Dismutase; Xeroderma Pigmentosum