4-hydroxy-2-nonenal and Lewy-Body-Disease

Lipoxidative damage of aldolase A, enolase 1, and glyceraldehyde dehydrogenase (GAPDH) was found in the frontal cortex in a percentage of aged controls by bidimensional gel electrophoresis, Western blot test, in-gel digestion, and mass spectrometry. Aldolase A and enolase 1 were altered in 12 of 19 cases, whereas oxidation of GAPDH was found in 6 of 19 controls. The three enzymes were oxidized in the frontal cortex in the majority of cases of incidental Parkinson's disease (iPD), PD, and dementia with Lewy bodies (DLB). Differences were statistically significant (chi(2) test) for GAPDH in PD and DLB. Densitometric studies have shown that the ratio of oxidized protein per spot is higher in iPD, PD, and DLB compared with controls. These findings show oxidation of three enzymes linked with glycolysis and energy metabolism in the adult human brain as well as increased oxidation of aldolase A, enolase 1, and GAPDH in the frontal cortex in Lewy body diseases. Modifications of these enzymes may result in decreased activity and may partly account for impaired metabolism and function of the frontal lobe in PD.

Topics: Aged; Aged, 80 and over; Aldehydes; Biomarkers, Tumor; Blotting, Western; Densitometry; DNA-Binding Proteins; Electrophoresis, Gel, Two-Dimensional; Energy Metabolism; Female; Frontal Lobe; Fructose-Bisphosphate Aldolase; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Humans; Lewy Body Disease; Male; Mass Spectrometry; Middle Aged; Oxidation-Reduction; Parkinson Disease; Phosphopyruvate Hydratase; Tumor Suppressor Proteins

Oxidative stress has been well documented in the substantia nigra in Parkinson disease (PD), but little is known about oxidative damage, particularly lipoxidation, advanced glycation (AGE), and AGE receptors (RAGE) in other structures, including the cerebral cortex, in early stages of diseases with Lewy bodies. The present study was undertaken to analyze these parameters in the frontal cortex (area 8), amygdala, and substantia nigra in selected cases with no neurologic symptoms and with neuropathologically verified incidental Lewy body disease-related changes, comparing them with healthy age-matched individuals. Results of the present study have shown mass spectrometric and immunologic evidences of increased lipoxidative damage by the markers malondialdehyde-lysine (MDAL) and 4-hydroxynonenal-lysine (HNE), increased expression of AGE in the substantia nigra, amygdala, and frontal cortex, and increased and heterogeneous RAGE cellular expression in the substantia nigra and frontal cortex in cases with early stages of parkinsonian neuropathology. In addition, increased content of the highly peroxidizable docosahexaenoic acid in the amygdala and frontal cortex. These changes were not associated to alpha-synuclein aggregation in cortex, contrasting with aggregates found in SDS-soluble fractions of frontal cortex in dementia with Lewy bodies (DLB) cases. The pattern of lipidic abnormalities differed in DLB and incidental Lewy body disease. Furthermore, although AGE and RAGE expression were raised in DLB, no increase in the total amount of HNE and MDAL adducts was found in the cerebral cortex in DLB. Preliminary analyses have identified 2 proteins with lipoxidative damage, alpha-synuclein and manganese superoxide dismutase (SOD2), in incidentally Lewy body disease cortex. This study demonstrates abnormal fatty acid profiles, increased and selective lipoxidative damage, and increased AGE and RAGE expression in the frontal cortex in cases with early stages of parkinsonian neuropathology without treatment. These findings further support antioxidant therapy in the treatment of PD to reduce cortical damage associated with oxidative stress.

Topics: Aged; Aged, 80 and over; Aldehydes; alpha-Synuclein; Blotting, Western; Docosahexaenoic Acids; Electrophoresis, Gel, Two-Dimensional; Fatty Acids; Female; Glycation End Products, Advanced; Humans; Immunohistochemistry; Lewy Body Disease; Male; Malondialdehyde; Mass Spectrometry; Neocortex; Nerve Tissue Proteins; Oxidative Stress; Parkinson Disease; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Synucleins

Multiple lines of evidence indicate that oxidative stress is a critical pathogenic factor in Parkinson disease (PD) and diffuse Lewy body disease (DLBD). Previously, we demonstrated increased levels of redox-active iron in Lewy bodies, and that Lewy bodies accumulate advanced glycation end-products. To further characterize the role of oxidative stress in diseases with Lewy body formation, we examined immunocytochemically eight cases of PD and five cases of DLBD for adducts of the lipid peroxidation adduct 4-hydroxy-2-nonenal, and for N(epsilon)-(carboxymethyl)lysine (CML). Our findings demonstrate immunolocalization of 4-hydroxynonenal and CML to Lewy bodies in PD and DLBD. These findings not only support prior studies indicating that lipid peroxidation is increased in patients with PD and DLBD but that oxidative damage may play a critical role in Lewy body formation.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Brain Stem; Humans; Immunohistochemistry; Lewy Body Disease; Lipid Peroxidation; Middle Aged; Neocortex; Neurons; Oxidative Stress; Parkinson Disease