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T J Montine

Publications and source records attributed to T J Montine.

At least 19 recordsLinked to original sources
PubMed2006

Selective dendritic degeneration of medium spiny neurons in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of dementia and shows more severely impaired performance on tests of executive functions compared to Alzheimer disease. Here the authors demonstrate selective spinodendritic degeneration of medium spiny neurons in regions of the caudate nucleus that subserve executive functions and propose that this may underlie, at least in part, the heightened executive dysfunction observed in patients with DLB.

Aged↗
PubMed2005

Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease.

Dysfunction of neostriatal medium spiny neurons (MSNs) is hypothesized to underlie late-stage motor complications of Parkinson disease (PD). The authors demonstrate shortened dendrite length of MSNs that was similar in four regions of neostriatum in late-stage PD. In contrast, MSN dendrite spine degeneration was unevenly distributed with the greatest loss in caudal putamen. The authors propose that these structural changes in MSN may contribute to late-stage motor complications of PD.

Aged↗
PubMed2004

Fragile X gene premutation in multiple system atrophy.

Previous reports have suggested that expansion of the CGG repeat located in the fragile X mental retardation 1 (FMR1) gene might be responsible for a significant number of patients with the multiple system atrophy (MSA) phenotype. Analysis of 65 MSA patients found only 4.6% displayed CGG expansions in the suspected range. This is similar to the frequency reported in the normal population, suggesting that this expansion does not play a major role in the MSA phenotype.

Aged↗
PubMed2004

Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: relevance to Parkinson's disease.

Maneb, a widely used fungicide, has been associated with Parkinsonism in humans. In experimental models, maneb and its major active element, manganese ethylene-bis-dithiocarbamate (Mn-EBDC) cause selective nigrostriatal neurodegeneration in mice and in rats, respectively. To investigate the mechanisms underlying this neurodegeneration, we studied the effects of Mn-EBDC on proteasomal function, which is decreased in patients with Parkinson's disease (PD), in a dopaminergic neuronal cell line (MES 23.5 or MES). The results demonstrated that exposure of MES cells to 6 microM Mn-EBDC for 7 days produced not only significant neurotoxicity but also inhibition of proteasomal chymotrypsin-like and postglutamyl peptidase activities. Proteasomal dysfunction was accompanied by formation of cytoplasmic inclusions that were positive for alpha-synuclein immunostaining and significantly increased sodium dodecyl sulfate-insoluble alpha-synuclein aggregation seen by Western blot analysis. In addition, there was a significant increase in oxidative stress, evidenced by elevated total protein carbonyl content, in cells treated with Mn-EBDC. Manipulation of intracellular reduced glutathione levels with N-acetyl-L-cysteine or L-buthionine sulfoximine pretreatment to modulate Mn-EBDC-mediated oxidative stress altered Mn-EBDC-mediated neurotoxicity, proteasomal dysfunction, and alpha-synuclein aggregation in these cells. These data suggest that neurotoxicity-induced by Mn-EBDC is at least partially attributable to Mn-EBDC-mediated proteasomal inhibition, and that the proteasome may be an important target by which environmental exposure modifies the risk for developing PD in vulnerable populations.

Amino Acid Sequence↗
PubMed2003

Lipoproteins and lipid peroxidation in Alzheimer's disease.

Alzheimer's Disease (AD) is a clinical-pathological entity that probably derives from different causes. Mounting evidence strongly implicates regionally increased oxidative damage to brain beyond what occurs with aging as one of the processes that may contribute to AD progression. While several different classes of molecules may be affected, lipid peroxidation is thought to be a prominent and especially deleterious form of oxidative damage in brain due to this organ's relative enrichment in polyunsaturated fatty acids. Our laboratory recently has demonstrated that lipoproteins in AD brain extracellular fluid are more vulnerable to oxidation than lipoproteins in control brain extracellular fluid. Apolipoprotein E (apoE) is the principal apolipoprotein in the central nervous system (CNS), and it serves as the major apolipoprotein that is capable of lipid transport and regulation of lipid metabolism through known receptor-mediated processes. Moreover, inheritance of the APOE4 allele represents the strongest genetic risk factor for sporadic AD. Evidence suggests that apoE isoforms may specifically influence the cellular distribution of lipid peroxidation products in brain and may therefore contribute to the stratification of risk for AD associated with APOE. Here, we review possible mechanisms whereby lipoprotein trafficking and lipid peroxidation converge to contribute to neurodegeneration in AD brain.

Aged↗
PubMed2002

The mitochondrial common deletion in Parkinson's disease and related movement disorders.

The mitochondrial 4977-bp common deletion has been reported in some studies to occur exclusively or with increased frequency in the midbrain of patients with Parkinson's disease (PD). Other studies could not confirm these results; rather, it was suggested that the mitochondrial common deletion is associated with aging in the midbrain and not PD. One possible explanation for these conflicting results is the difficulty in quantifying mitochondrial DNA deletions or mutations in the whole midbrain or substantia nigra (SN) while only a subset of midbrain neurons degenerate in PD. In addition, none of the studies has addressed the cell types with the common deletion within the midbrain. In this study we used in situ hybridization to detect the common deletion in sections of midbrain from patients with PD, multiple system atrophy-parkinsonian type (MSA-P), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), age-matched controls, and individuals of different ages. The results demonstrated that the mitochondrial common deletion accumulated primarily in neurons but not glia in both the SN and other midbrain regions. There was no significant difference in the number or distribution of neurons with the common deletion or the average of the mean densities (AMD) of staining with the common deletion in nigral neurons among patients with PD, MSA-P, PSP, DLB, or age-matched controls. In addition, there was no difference in the number or distribution of neurons with the common deletion in nigral neurons between any age group, although there was a tendency for the common deletion to increase in the non-nigral neurons in older patients. These data indicate that accumulation of the 4977-bp common deletion in mitochondrial DNA in midbrain occurred primarily in neurons, and by this cytological approach, it was not associated with nigral neurodegeneration in the common movement disorders or aging.

Adolescent↗
PubMed2002

CSF lipoproteins and Alzheimer's disease.

Alterations in lipid homeostasis have been suggested to play a role in the pathogenesis of Alzheimer's disease (AD). This hypothesis is supported by the observed changes in lipid content and composition of AD brains when compared to age-matched control brains. The association between the e4 allele of the apolipoprotein E gene and increased risk of AD implicates lipoproteins in the pathogenesis. Lipoproteins are macromolecular particles responsible for lipid trafficking and metabolism. CNS lipoproteins are different from their plasma counter parts. We review the current understanding of the structure and functions of CNS lipoproteins. In addition to mediating lipid trafficking and metabolism, there is increasing evidence that apoE-containing lipoproteins are also involved in dendritic remodeling and synaptogensis and maintenance of the synapto-dendritic complexity during aging. Interestingly, these functions have been shown to be apoE-isoform specific with apoE4 lacking the activities of apoE3 and apoE2. In addition to the association between apoE4 and an increased risk of AD, oxidative stress is believed to play a role in the pathogenesis of this disease. Indeed evidence of lipid peroxidation in cerebral spinal fluid (CSF) lipoproteins from AD patients has been observed. Oxidation of lipoproteins not only eliminates their supportive roles in neurite outgrowth and synaptogenesis, but actually transforms them into neurotoxic agents. The elucidation of the pathways and mechanisms by which apoE-isoform and oxidation affect lipoprotein function in the CNS remains a challenge for scientist in the field of neurodegenerative disease.

Alzheimer Disease↗
PubMed2001

Elevation of AKR7A2 (succinic semialdehyde reductase) in neurodegenerative disease.

Elevated levels of oxidative stress or decreased antioxidant defense mechanisms may underlie the regionally increased oxidative damage to brain observed in many neurodegenerative disorders. Phase I detoxification pathways for reactive aldehydes generated from lipid peroxidation include aldehyde dehydrogenases, alcohol dehydrogenases and aldo-keto reductases (AKR). In the present study, we examined the cellular expression of AKR family member, succinic semialdehyde reductase (AKR7A2) that reduces toxic aldehydes as well as catalyzing the biosynthesis of the neuromodulator gamma-hydroxybutyrate (GHB). Our results show that in the cerebral cortex and hippocampus, AKR7A2 is primarily localized to glial cells, astrocytes and microglia. In the midbrain, AKR7A2 was found in glia and neuromelanin-containing neurons of the substantia nigra, and the periaqueductal gray. In sections of cerebral cortex and hippocampus from patients with AD and DLB, AKR7A2 immunoreactivity was elevated in reactive astrocytes and microglial cells. Furthermore, total AKR7A2 protein levels were elevated in the cerebral cortex of patients with AD versus control individuals. Our data suggest that reactive gliosis, as a response to injury, may affect GHB neuromodulatory pathways in neurodegenerative disease and elevate aldehyde detoxification pathways.

Aged↗
PubMed2001

Interactions between apolipoprotein E gene and dietary alpha-tocopherol influence cerebral oxidative damage in aged mice.

Cerebral oxidative damage is a feature of aging and is increased in a number of neurodegenerative diseases. We pursued the gene-environment interaction of lack of apolipoprotein E (apoE) and modulation of dietary alpha-tocopherol on cerebral oxidative damage in aged male and female mice by quantifying the major isomers of cerebral isoprostanes, derived from arachidonic acid (AA) oxidation, and neuroprostanes, derived from docosahexaenoic acid (DHA) oxidation. Mice fed alpha-tocopherol-deficient, normal, or -supplemented diet had undetectable, 4486 +/- 215, or 6406 +/- 254 ng of alpha-tocopherol per gram of brain tissue (p < 0.0001), respectively. Two factors, male gender and lack of apoE, combined to increase cerebral AA oxidation by 28%, whereas three factors, male gender, lack of apoE, and deficiency in alpha-tocopherol, combined to increase cerebral DHA oxidation by 81%. alpha-Tocopherol supplementation decreased cerebral isoprostanes but not neuroprostanes and enhanced DHA, but not AA, endoperoxide reduction in vivo and in vitro. These results demonstrated that the interaction of gender, inherited susceptibilities, and dietary alpha-tocopherol contributed differently to oxidative damage to cerebral AA and DHA in aged mice.

Administration, Oral↗
PubMed2001

Expression of glutathione-S-transferase isozyme in the SY5Y neuroblastoma cell line increases resistance to oxidative stress.

Glutathione-S-transferases (GSTs) are a superfamily of enzymes that function to catalyze the nucleophilic attack of glutathione on electrophilic groups of a second substrate. GSTs are present in many organs and have been implicated in the detoxification of endogenous alpha, beta unsaturated aldehydes, including 4-hydroxynonenal (HNE). Exogenous GST protects hippocampal neurons against HNE in culture. To test the hypothesis that overexpression of GST in cells would increase resistance to exogenous or endogenous HNE induced by oxidative stress, stable transfectants of SY5Y neuroblastoma cells with GST were established. Stable GST transfectants demonstrated enzyme activities 13.7 times (Clone 1) and 30 times (Clone 2) higher than cells transfected with vector alone. GST transfectants (both Clones 1 and 2) demonstrated significantly (p <.05) increased resistance to ferrous sulfate/hydrogen peroxide (20.9% for Clone 1; 46.5% for Clone 2), amyloid beta-peptide (12.2% for Clone 1; 27.5.% for Clone 2), and peroxynitrite (24.3% for Clone 1; 43.9% for Clone 2), but not to exogenous application of HNE in culture medium. GST transfectants treated with 1,1,4-tris (acetyloxy)nonane, a nontoxic derivative of HNE that is degraded to HNE intracellularly, demonstrated a statistically significant (p <.05) increase in viability in a dose-dependent manner compared with SY5Y cells transfected with vector alone. These results suggest that overexpression of GST increases resistance to endogenous HNE induced by oxidative stress or released in the degradation of 1,1,4-tris (acetyloxy)nonane, but not to exogenous application of HNE.

Aldehydes↗
PubMed2001

Formation of highly reactive gamma-ketoaldehydes (neuroketals) as products of the neuroprostane pathway.

Neuroprostanes are prostaglandin-like compounds produced by free radical-induced peroxidation of docosahexaenoic acid, which is highly enriched in the brain. We previously described the formation of highly reactive gamma-ketoaldehydes (isoketals) as products of the isoprostane pathway of free radical-induced peroxidation of arachidonic acid. We therefore explored whether isoketal-like compounds (neuroketals) are also formed via the neuroprostane pathway. Utilizing mass spectrometric analyses, neuroketals were found to be formed in abundance in vitro during oxidation of docosahexaenoic acid and were formed in greater abundance than isoketals during co-oxidation of docosahexaenoic and arachidonic acid. Neuroketals were shown to rapidly adduct to lysine, forming lactam and Schiff base adducts. Neuroketal lysyl-lactam protein adducts were detected in nonoxidized rat brain synaptosomes at a level of 0.09 ng/mg of protein, which increased 19-fold following oxidation in vitro. Neuroketal lysyl-lactam protein adducts were also detected in vivo in normal human brain at a level of 9.9 +/- 3.7 ng/g of brain tissue. These studies identify a new class of highly reactive molecules that may participate in the formation of protein adducts and protein-protein cross-links in neurodegenerative diseases and contribute to the injurious effects of other oxidative pathologies in the brain.

Animals↗
PubMed2001

Acrolein inhibits respiration in isolated brain mitochondria.

Lipid peroxidation is elevated in diseased regions of brain in several neurodegenerative diseases. Acrolein (2-propenal) is a major cytotoxic product of lipid peroxidation and its adduction to neuronal proteins has been demonstrated in diseased brain regions from patients with Alzheimer's disease. Mitochondrial abnormalities are implicated in several neurodegenerative disorders, and mitochondria are targets of alkenal adduction in vivo. We examined the effects of acrolein upon multiple endpoints associated with the mitochondrial involvement in neurodegenerative disease. Acrolein inhibited state 3 respiration with an IC(50) of approx. 0.4 micromol/mg protein; however, there was no reduction in activity of complexes I-V. This inhibition was prevented by glutathione and N-acetylcysteine. Acrolein did not alter mitochondrial calcium transporter activity or induce cytochrome c release. These studies indicate that acrolein is a potent inhibitor of brain mitochondrial respiration.

Acrolein↗
PubMed2001

Brain regional quantification of F-ring and D-/E-ring isoprostanes and neuroprostanes in Alzheimer's disease.

Isoprostanes (IsoP) are produced exclusively from free radical damage to arachidonic acid, a fatty acid that is evenly distributed throughout white matter and gray matter, whereas neuroprostanes (NPs) are generated analogously from docosahexaenoic acid (DHA), a fatty acid enriched in gray matter where it is concentrated in neurons. IsoP and NPs derive from endoperoxide intermediates that isomerize to D/E-ring forms or that are reduced to F-ring compounds. We quantified F-ring and D/E-ring IsoP and NPs in temporal and parietal cortex, hippocampus, and cerebellum of nine definite Alzheimer's disease (AD) patients and 11 age-matched controls. Total NP levels (F-ring plus D/E-ring), but not total IsoP, were significantly greater in AD than controls (P: < 0.0001); only cerebral regions in AD patients had NPs greater than controls (P: < 0.05). The F-ring to D/E-ring ratio for NPs, but not IsoP, was 40 to 70% lower in all brain regions of AD patients compared to controls (P: < 0.005). These data extend results from in situ techniques, that have localized reactive products of lipid peroxidation primarily to neurons, by quantifying significantly greater free radical damage to the DHA-containing compartments in cerebrum in AD patients than controls, and suggest that one mechanism of increased oxidative stress may be diminished reducing capacity in DHA-containing compartments.

Alleles↗
PubMed2001

Improved assay for the quantification of the major urinary metabolite of the isoprostane 15-F(2t)-Isoprostane (8-iso-PGF(2alpha)) by a stable isotope dilution mass spectrometric assay.

BACKGROUND: The F(2)-isoprostanes (IsoPs) are a series of novel prostaglandin (PG)-like compounds generated from the free radical catalyzed peroxidation of arachidonic acid. One IsoP, 15-F(2t)-IsoP (8-iso-PGF(2alpha)), has been shown to be formed in abundance in vivo and to exert potent biological activity. METHODS: As a means to assess the endogenous production of this compound, we previously developed a method to quantify the major urinary metabolite of 15-F(2t)-IsoP, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (2,3-dinor-5,6-dihydro-8-iso-PGF(2alpha), 15-F(2t)-IsoP-M ), by gas chromotography (GC)/negative ion chemical ionization mass spectrometry (MS) employing stable isotope dilution methodology. While useful, we found that the assay occasionally suffered from the presence of impurities that co-elute on GC with 15-F(2t)-IsoP-M, making the measurement of this compound difficult. We now report a modified assay for the quantification of 15-F(2t)-IsoP-M employing GC/MS that alleviates this problem. RESULTS: Precision of the assay is +/-7% and the accuracy is 96%. The lower limit of sensitivity is approximately 8 pg. Normal concentrations of this metabolite in urine were found to be 0.46+/-0.09 ng/mg creatinine (mean+/-1 S.D.) Urinary excretion of 15-F(2t)-IsoP-M is markedly altered in situations associated with increased or decreased oxidant stress in vivo. CONCLUSIONS: This assay provided a sensitive and accurate method to assess endogenous IsoP generation and can be used to further explore the role of oxidant injury in human disease.

Chromatography, Gas↗
PubMed2001

Cysteine and mercapturate conjugates of oxidized dopamine are in human striatum but only the cysteine conjugate impedes dopamine trafficking in vitro and in vivo.

Recent results have suggested that some products of mercapturic acid pathway (MAP) metabolism of oxidized dopamine (DA) may contribute to mesostriatal dopaminergic neurodegeneration, and that at least one product, 5-S-cysteinyldopamine (Cys-DA), is elevated in patients with advanced Parkinson's disease (PD) who have been treated with L-DOPA. Here we investigated MAP enzymes and products in the midbrain and striatum of control individuals and patients with dementia with Lewy bodies (DLB) who had less severe dopaminergic degeneration than PD patients and who were not treated with L-DOPA. We also determined the biological activity of MAP metabolites of oxidized DA using primary rat mesencephalic cultures, rat cerebral synaptosomes, and rat striatum in vivo microdialysis. Our results showed that the human mesostriatal dopaminergic pathway generates Cys-DA but has limited enzymatic capacity for mercapturate formation, that striatal levels of MAP products of oxidized DA are not elevated in DLB patients compared with controls, and that Cys-DA interferes with trafficking of DA in vitro and in vivo. These results indicate that while Cys-DA is not increased in striatum of patients with mild dopaminergic neurodegeneration, it may interfere with uptake of DA in patients with advanced PD.

Acetylcysteine↗
PubMed2001

Expression and activities of aldo-keto oxidoreductases in Alzheimer disease.

A reactive intermediate generated by lipid peroxidation, 4-hydroxy-2-nonenal (HNE), has received considerable attention as a potential effector of oxidative damage and Abeta peptide-mediated neurotoxicity in Alzheimer disease (AD). However, little is known about aldo-keto oxidoreductases, a group of enzymes that constitute a major detoxifying pathway for HNE and related reactive aldehydes in human brain. We have determined the regional, cellular, and class distribution in human brain of the 4 major aldo-keto oxidoreductases that detoxify HNE: aldehyde dehydrogenase (ALDH): aldose reductase; aldehyde reductase: and alcohol dehydrogenase (ADH). Of these 4 enzymes, only ALDH and aldose reductase were expressed in cerebral cortex. hippocampus, basal ganglia, and midbrain: all 4 enzymes were present in cerebellum. In cerebrum and hippocampus, aldose reductase was localized to pyramidal neurons and mitochondrial class 2 ALDH was localized to glia and senile plaques. ALDH, but not aldose reductase, activity was significantly increased in temporal cortex from patients with AD compared to age-matched controls. These results suggest that in brain regions involved in AD, neurons and glia utilize different mechanisms to detoxify HNE, and that increased ALDH activity is a protective response of cerebral cortex to AD.

Alcohol Dehydrogenase↗
PubMed2001

Dopamine thioethers in neurodegeneration.

Dopamine oxidation is proposed to be a significant contributor to mesostriatal dopaminergic neurodegeneration, although the mechanisms are not fully resolved. Recent results from in vitro and in vivo models have suggested that some products from mercapturic acid pathway (MAP) metabolism of oxidized dopamine (DA) may contribute to dopaminergic neurodegeneration, and that at least one product of this pathway, 5-S-cysteinyldopamine (Cys-DA), is elevated in patients with advanced Parkinson's disease (PD). Here we review recent findings on MAP enzymes and their products in rodent brain and in diseased regions of brain from patients with mesostriatal dopaminergic neurodegeneration. We also review the current data and our recent findings on the neurobiological activity of MAP metabolites of oxidized DA. We conclude that human striatum has limited enzymatic capacity for mercapturate formation, that levels of MAP products of oxidized DA are significantly elevated in PD patients with advanced dopaminergic neurodegeneration but not in patients with less severe degeneration, and that Cys-DA interferes with trafficking of DA in vitro and in vivo. These results indicate that Cys-DA may interfere with DAtrafficking in patients with advanced dopaminergic neurodegeneration.

Acetylcysteine↗