Homocysteine metabolism and various consequences of folate deficiency
Authors: Tchantchou, Flaubert
Article Type: Research Article
Abstract: Homocysteine is a neurotoxic non-proteinogenic amino acid, an abnormal increase of which in plasma has been implicated in many pathological conditions including cardiovascular diseases, neural tube defects and is now recognized and Alzheimer's disease. Homocysteine elimination is regulated by the transmethylation and the transsulfuration pathways and is modulated by folate, a member of the B-vitamin family. A metabolic product of folate, 5 methyltetrahydrofolate, provides a methyl group that is used to reconvert homocysteine back to methionine through the transmethylation pathway. The efficiency of folate metabolism has an impact on the availability of S-adenosylmethionine (SAM), a compound that is known to …activate homocysteine flux through the transsulfuration pathway. SAM is also necessary for utilization of the antioxidant glutathione via glutathione S-transferase. In this review, I will elaborate on different biochemical reactions that are implicated in the regulation of homocysteine elimination through the transmethylation and the transsulfuration pathways and on various consequences of folate deficiency on homocysteine metabolism. Show more
Keywords: Alzheimer's disease, folic acid, homocysteine, s-adenosylmethione (SAM)
DOI: 10.3233/JAD-2006-9408
Citation: Journal of Alzheimer's Disease, vol. 9, no. 4, pp. 421-427, 2006
S-Adenosylmethionine Mediates Glutathione Efficacy by Increasing Glutathione S-Transferase Activity: Implications for S-Adenosyl Methionine as A Neuroprotective Dietary Supplement
Authors: Tchantchou, Flaubert | Graves, Michael | Falcone, Deane | Shea, Thomas B.
Article Type: Research Article
Abstract: When maintained on a folate-deficient, iron-rich diet, transgenic mice lacking in apolipoprotein E (ApoE–/– mice) demonstrate impaired activity of glutathione S-transferase (GST), resulting in increased oxidative species within brain tissue despite abnormally high levels of glutathione. These mice also exhibit reduced levels of S-adenosyl methionine (SAM) and increased levels of its hydrolysis product S-adenosyl homocysteine, which inhibits SAM usage. Supplementation of the above diet with SAM restored GST activity and eliminated reactive oxygen species at the expense of stockpiled glutathione, suggesting that one or more SAM-dependent reactions were required to maintain GST activity. We examined herein the impact of SAM …on GST activity using a cell-free assay. SAM stimulated GST activity in a dose-response manner when added to homogenates derived from the above ApoE–/– mice. SAM also increased activity of purified rat liver GST and recombinant GST. Filtering of SAM through a 4kDa cutoff and systematic withholding of reaction components eliminated the possibility of any additional contaminating enzyme. These findings confirm that SAM can exert a direct effect on GST activity. Since Alzheimer's disease is accompanied by reduced GST activity, diminished SAM and increased SAH, these findings underscore the critical role of SAM in maintenance of neuronal health. Show more
Keywords: Alzheimer's disease, apolipoprotein E, glutathione, methylation, oxidative stress, S-adenosyl methionine
DOI: 10.3233/JAD-2008-14306
Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 323-328, 2008
Apple juice concentrate prevents oxidative damage and impaired maze performance in aged mice
Authors: Tchantchou, Flaubert | Chan, Amy | Kifle, Lydia | Ortiz, Daniela | Shea, Thomas B.
Article Type: Research Article
Abstract: Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of fruits and vegetables rich in antioxidant can provide superior protection than supplementation with purified antioxidants. Our prior studies have shown that supplementation with apple juice concentrate (AJC) alleviates oxidative damage and cognitive decline in a transgenic murine model compromised in endogenous antioxidant potential when challenged with a vitamin-deficient, oxidative stress-promoting diet. Herein, we demonstrate that AJC, administered in drinking water, is neuroprotective in normal, aged mice. Normal mice aged either 9–10 months or 2–2.5 years were maintained for 1 month on a complete diet or a diet lacking …folate and vitamin E and containing iron as a pro-oxidant, after which oxidative damage was assayed by thiobarbituric acid-reactive substances and cognitive decline as assayed by performance in a standard Y-maze. Mice 9–12 months of age were unaffected by the deficient diet, while older mice demonstrated statistically-increased oxidative damage and poorer performance in a Y maze test. Supplementation with AJC prevented these neurodegenerative effects. These data are consistent with normal aged individuals being susceptible to neurodegeneration following dietary compromise such as folate deficiency, and a hastened onset of neurodegeneration in those individuals harboring a genetic risk factor such as ApoE deficiency. These findings also support the efficacy of antioxidant supplementation, including consumption of antioxidant-rich foods such as apples, in preventing the decline in cognitive performance that accompanies normal aging. Show more
Keywords: Aging, neurodegeneration, antioxidants, cognitive decline, nutrition, apple juice
DOI: 10.3233/JAD-2005-8306
Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 283-287, 2005
N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency
Authors: Tchantchou, Flaubert | Graves, Michael | Rogers, Eugene | Ortiz, Daniela | Shea, Thomas B.
Article Type: Research Article
Abstract: Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1 g/kg diet), a cell-permeant antioxidant and GSH precursor, …alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders. Show more
Keywords: N-acteyl cysteine, glutathione, folate, vitamin E, neurodegeneration, oxidative stress, apolipoprotein E
DOI: 10.3233/JAD-2005-7206
Citation: Journal of Alzheimer's Disease, vol. 7, no. 2, pp. 135-138, 2005
Stimulation of Neurogenesis and Synaptogenesis by Bilobalide and Quercetin via Common Final Pathway in Hippocampal Neurons
Authors: Tchantchou, Flaubert | Lacor, Pascale N. | Cao, Zhiming | Lao, Lixing | Hou, Yan | Cui, Changhai | Klein, William L. | Luo, Yuan
Article Type: Research Article
Abstract: Loss of synapses has been correlated with dementia in Alzheimer's disease (AD) as an early event during the disease progression. Hence, synaptogenesis and neurogenesis in adulthood could serve as a therapeutic target for the prevention and treatment of AD. Recently, we have demonstrated enhanced hippocampal neurogenesis by oral administration of Ginkgo biloba extract (EGb 761) to a mouse model of AD. This study aims to identify the constituents that contribute to EGb 761-induced neurogenesis. Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of …cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-β oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation. Show more
Keywords: Amyloid-beta derived diffusible ligands (ADDL), bilobalide, CREB, neurogenesis, quercetin, synaptogenesis
DOI: 10.3233/JAD-2009-1189
Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 787-798, 2009