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Thomas B Shea

Publications and source records attributed to Thomas B Shea.

44 records · Page 3Linked to original sources
PubMed2002

Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage.

Homocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD). We examined the consequences of treatment of cultured murine cortical neurons with HC. Homocysteine-induced increases in cytosolic calcium, reactive oxygen species, phospho-tau immunoreactivity and externalized phosphatidyl serine (indicative of apoptosis). Homocysteine-induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity, as evidenced by treatment with antagonists of the NMDA channel and metabotropic glutamate receptors, respectively. The NMDA channel antagonist MK-801 reduced tau phosphorylation but not apoptosis after HC treatment, suggesting that HC-mediated apoptosis was not due to calcium influx. Apoptosis after HC treatment was reduced by co-treatment with 3-aminobenazmidine (3ab), an inhibitor of poly-ADP-ribosome polymerase (PARP), consistent with previous reports that ATP depletion by PARP-mediated repair of DNA strand breakage mediated HC-induced apoptosis. Treatment with 3ab did not reduce tau phosphorylation, however, therefore hyperphosphorylation of tau may not contribute to HC-induced apoptosis under these conditions. Inhibition of mitogen-activated protein kinase by co-treatment with the kinase inhibitor PD98059 inhibited tau phosphorylation but not apoptosis after HC treatment. HC accumulation reduces cellular levels of S-adenosyl methionine (SAM); co-treatment with SAM reduced apoptosis, suggesting that inhibition of critical methylation reactions may mediate HC-induced apoptosis. These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes.

Animals↗
PubMed2002

Apolipoprotein E deficiency promotes increased oxidative stress and compensatory increases in antioxidants in brain tissue.

The epsilon 4 allele of the apolipoprotein E gene (ApoE) is associated with Alzheimer's disease (AD). The extent of oxidative damage in AD brains correlates with the presence of the E4 allele of ApoE, suggesting an association between the ApoE4 genotype and oxygen-mediated damage in AD. We tested this hypothesis by subjecting normal and transgenic mice lacking ApoE to oxidative stress by folate deprivation and/or excess dietary iron. Brain tissue of ApoE-deficient mice displayed increased glutathione and antioxidant levels, consistent with attempts to compensate for the lack of ApoE. Folate deprivation and iron challenge individually increased glutathione and antioxidant levels in both normal and ApoE-deficient brain tissue. However, combined treatment with folate deprivation and dietary iron depleted antioxidant capacity and induced oxidative damage in ApoE-deficient brains despite increased glutathione, indicating an inability to compensate for the lack of ApoE under these conditions. These data support the hypothesis that ApoE deficiency is associated with oxidative damage, and demonstrate a combinatorial influence of genetic predisposition, dietary deficiency, and oxidative stress on oxidative damage relevant to AD.

Alzheimer Disease↗
PubMed2002

Efficacy of vitamin E, phosphatidyl choline, and pyruvate on buffering neuronal degeneration and oxidative stress in cultured cortical neurons and in central nervous tissue of apolipoprotein E-deficient mice.

Oxidative stress is a pivotal factor in neuronal degeneration. However, vitamin E was only marginally effective in clinical trials. We examined whether or not a mixture of vitamin E (as alpha-tocopherol), sodium pyruvate and phosphatidyl choline (PC), a mixture that promotes wound healing in non-neuronal systems, would provide neuroprotection beyond that observed with vitamin E alone. Combined treatment with these agents improved survival and neuritic spouting of murine embryonic cortical neurons in culture, and provided neuroprotection against oxidative damage following treatment with hydrogen peroxide. Dietary treatment with these three agents also compensated for the diminished oxidative buffering capacity of brains of apolipoprotein E-deficient mice, while vitamin E alone failed to do so. These data underscore the possibility that critical nutritional deficiencies may modulate the impact of genetic compromise on neurodegeneration.

Animals↗
PubMed2002

Folate quenches oxidative damage in brains of apolipoprotein E-deficient mice: augmentation by vitamin E.

We demonstrate that folate and vitamin E can compensate for the diminished oxidative buffering capacity of brains of apolipoprotein E-deficient mice. Normal and ApoE(tmlUne) homozygous 'knockout' mice were maintained for 1 month on a diet either lacking or supplemented with folate, vitamin E or iron as a pro-oxidant after which brain tissue was harvested and analyzed for for thiobarbituric acid-reactive substances (TBARs) as an index of oxidative damage. Normal mice exhibited no significant difference in TBARs following iron challenge in the presence or absence of vitamin E, folic acid or both. Similarly, ApoE knockout mice exhibited no significant differences following dietary iron challenge in the presence or absence of vitamin E. However, ApoE knockout mice accumulated significantly increased TBARs following iron challenge when folic acid was withheld, and accumulated even more TBARs when both folic acid and vitamin E were withheld. These findings demonstrate that ApoE knockout mice during vitamin deficiency are less capable of buffering the consequences of dietary iron challenge than are normal mice. Since the apolipoprotein E4 allele, which exhibits diminished oxidative buffering capacity, is linked to Alzheimer's disease (AD), these data underscore the possibility that critical nutritional deficiencies may modulate the impact of genetic compromise on neurodegeneration in AD.

Animals↗
PubMed2002

Acetyl-L-carnitine protects against amyloid-beta neurotoxicity: roles of oxidative buffering and ATP levels.

Acetyl-L-carnitine (ALCAR), normally produced in mitochondria, is a precursor of acetyl-CoA in the tricarboxylic (TCA) cycle. Since mitochondrial compromise and ATP depletion have been considered to play a role in neuronal degeneration in Alzheimer's disease (AD), we examined whether ALCAR attenuated oxidative stress and/or ATP depletion after exposure of cells to beta-amyloid (Abeta), a neurotoxic peptide that accumulates in AD brain. Differentiated SH-SY-5Y human neuroblastoma cells were exposed for 2-24 h to 20 microM Abeta in the presence and absence of 50 microM ALCAR. ALCAR attenuated oxidative stress and cell death induced by Abeta neurotoxicity. Abeta depleted ATP levels, suggesting Abeta may induce neurotoxicity in part by compromising neuronal energy. ALCAR prevented ATP depletion; therefore, ALCAR may mediate its protective effect by buffering oxidative stress and maintaining ATP levels.

Acetylcarnitine↗
PubMed2002

Homocysteine, folate deprivation and Alzheimer neuropathology.

Increased levels of homocysteine (HC), arising in some situations via deficiencies in folate--an essential cofactor in metabolic regulation of HC--have long been known to contribute to cardiovascular disorders and stroke. More recently, clinical studies implicate increased HC and reduced folate with neurodegenerative conditions including Alzheimer's disease. It has remained unclear from clinical studies whether the neurotoxicity of increased HC and/or reduced folate is derived from direct detrimental effects on neurons themselves, or is instead derived indirectly following perturbation of nervous system vasculature. However, recent reports from several laboratories provide evidence that HC not only induces direct neurotoxicity, but also potentiates both amyloid-beta and glutamate neurotoxicity. These latter studies leave open the possibility that even mild elevations in HC may place neurons at risk for additional trauma. The potential contribution of folate deficiency and resultant increases in HC to neurodegeneration in AD, and therapeutic approaches to alleviate their impact, is discussed.

Alzheimer Disease↗
PubMedDate not supplied

Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: modulation by apolipoprotein E-deficiency.

Folate deficiency increases neuronal oxidative damage and potentiates the deleterious effects of apolipoprotein E (ApoE) deficiency. Mice lacking ApoE (ApoE -/- mice) upregulate the expression and activity of another enzyme, glutathione synthase (GS), when deprived of folate, in an apparent attempt to compensate for increased oxidative damage. Herein, we examined the influence of ApoE and folate deficiency on expression and activity of several enzymes of the methionine cycle. Expression and activity of methylene tetrahydrofolate reductase was increased in the order ApoE +/+ < ApoE +/- < ApoE -/- in response to folate deprivation. Expression of cystathione beta synthase followed a similar pattern. By contrast, expression and activity of methionine synthase decreased following folate deprivation in the order ApoE +/+ < ApoE +/- < ApoE -/-. These studies demonstrate that folate deficiency induces compensatory regulation of methionine cycle genes, and that these effects are potentiated by ApoE deficiency in a gene-dosage manner. They further support the notion that latent genetic deficiencies, including those of methionine cycle, may contribute to Alzheimer's disease, especially in concert with age-related nutritional deficiencies.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗