The Emerging Role of Glutathione in Alzheimer's Disease

Saharan, Sumiti; Mandal, Pravat K.

doi:10.3233/jad-132483

Cited by 154 publications

(109 citation statements)

References 114 publications

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“…Hence, it is not possible to establish whether the presence of the virus is responsible for the neuronal alterations observed (31). Actually, we could not establish the cause of the GSH depletion found, but we suggest that it may contribute to the neuronal alterations described in MAIDS, as has already been observed in other neurodegenerative disorders, such as Alzheimer's disease (56). This aspect is worth further investigation; in fact, it would be interesting to evaluate the capacity of GSH precursors able to cross the blood-brain barrier to diminish the encephalopathy that develops in these mice by replenishment of GSH levels (57).…”

Section: Discussioncontrasting

confidence: 44%

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152),an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCEThe first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/ Th2 imbalance to be more effectively combated. Infection with the LP-BM5 murine leukemia virus causes a profound and broad immunodeficiency in susceptible mouse strains, such as C57BL/6 (B6) mice. This disease is known as murine AIDS (MAIDS) and is characterized by early polyclonal T-and B-cell activation, splenomegaly, lymphadenopathy, hypergammaglobulinemia, decreased T-and B-cell responses, increased susceptibility to opportunistic pathogens, and the development of terminal B-cell lymphomas and neurological dysfunctions (1-4). MAIDS is charact...

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Section: Discussioncontrasting

confidence: 44%

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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“…The critical role of GSH in maintaining the redox state of proteins essential for DNA repair and expression in the nucleus, detoxifying foreign compounds in the cytosol, and protecting mitochondrial DNA damage are well-established (de la Asuncion et al, 1996, Saikat andRaja, 2011). In fact, GSH has been used as a biomarker in various oxidative stress-related diseases (Romeu et al, 2010, Saharan and Mandal, 2014.…”

Section: Antioxidants As Biomarkers Of Oxidative Stressmentioning

confidence: 99%

“…In fact, GSH is the most abundant endogenous antioxidant due to its marked ability to scavenge ROM and free radicals. Hence, concentration of GSH has been used as biomarker in various oxidative stress-related diseases (Romeu et al, 2010, Saharan and Mandal, 2014. The overall decrease in total and reduced GSH concentration after parturition could have been due to the increased production of ROM and free radicals.…”

Section: Biomarkers Of Oxidative Stressmentioning

confidence: 99%

“…Hence, hepatic concentrations of GSH and taurine have been widely-used as oxidative stress biomarkers (Romeu et al, 2010, Saharan and Mandal, 2014. It is noteworthy that liver is the main site of taurine synthesis and releases taurine into plasma (Garcia and Stipanuk, 1992), but not for transport to other tissues (Hayes and Sturman, 1981).…”

Section: Sulfur-containing Compound Pool and Metabolismmentioning

confidence: 99%

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049 Physiological and molecular mechanisms associated with performance, immunometabolic status, and liver function in transition dairy cows fed rumen-protected methionine or choline

Zhou

Vailati-Riboni

Bulgari

et al. 2016

Journal of Animal Science

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The onset of lactation in dairy cows is characterized by high output of methylated compounds in milk when sources of methyl group are in short supply. Methionine (MET) and choline (CHOL) are key methyl donors and their availability during this time may be limiting for milk production, hepatic lipid metabolism, and immune function. Supplementing rumenprotected MET and CHOL may improve overall performance and health of transition cows. observed in response to CHOL supplementation, expression of (BHMT) and MTR and BHMT enzyme activity did not change (P > 0.05). Furthermore, overall MTR enzyme activity was lower (23.5 vs. 29.6 nmol product h -1 mg protein -1 ; SEM = 2.9; P = 0.05) in CHOL cows. In terms of AA profile, MET supplementation led to greater (P < 0.01) circulating methionine and proportion of methionine in the essential AA pool, total AA, and total sulfur-containing compounds. Lysine in total AA also tends to be greater (P = 0.08) in these cows, indicating a better overall AA profile. Sulfur-containing compounds (cystathionine, cystine, homocystine, and taurine) also were greater (P < 0.05) in MET-supplemented cows, indicating an enriched sulfur-containing compound pool due to enhanced transsulfuration activity. Circulating essential AA (P = 0.06) and total AA (P = 0.03) concentrations were greater in MET cows due to greater lysine, arginine, tryptophan, threonine, proline, asparagine, alanine, and citrulline. In contrast, tryptophan and cystine were greater. Plasma 3-methylhistidine concentration was lower (P = iv 0.02) in response to CHOL, suggesting less tissue protein mobilization in these cows. Overall, results indicate that MET supplementation improves performance of transition cows through a combination of better immunometabolic status, plasma AA profile, and a reduction in oxidative stress; insufficient regeneration of MET may be one reason for the lack of effect with supplemental CHOL.

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“…Notably, AD is often accompanied by a decrease of the activity and/or the levels of antioxidant enzymes such as Superoxide dismutase (SOD), Glutathione reductase, Glutathione peroxidase and Glutathione-Stransferase (GST). It is also clear that AD pathology is associated with disruptions in GSH homeostasis, the most prevalent antioxidant in brain [89].…”

Section: Involvement Of Sam In Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

Cavallaro¹,

Fuso²,

D’Erme³

et al. 2016

Int J Clin Nutr Diet

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S-adenosyl-L-methionine (SAM) is the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. SAM level in the organism decreases with aging and restoring the original levels through exogenous supplementation is an important tool for the improvement of many vital functions. Indeed, SAM deficiency may contribute to the onset of several diseases, i.e. depression, liver diseases, osteoarthritis and senile neurological disorders such as Alzheimer's and Parkinson's diseases. Recent evidences indicate that SAM may have an involvement in oxidative stress, a process which typically involves an alteration of cellular sulfur amino acids homeostasis. SAM is not only the principal methyl donor, but also a precursor of glutathione, the major endogenous antioxidant, whose role in counteracting oxidative stress is well known. In this review we will highlight the role of SAM not just as a methyl-donor but also as a regulator of different metabolic pathways involved in the antioxidant response in brain related disorders. Role of S-adenosylmethionine in the Modulation of Oxidative StressRelated Neurodegeneration Review ArticleOpen Access IntroductionThe interaction between environmental and genetic factors plays a fundamental role in inducing and modulating the aging processes towards brain disorders. Among environmental factors, diet and nutritional lifestyle have a key role in brain health through the alteration of the intake or the bioavailability of metabolites and cofactors. Specific nutritional factors have particular impact on one-carbon metabolism, which is a complex biochemical pathway regulated by the presence of folate, vitamin B12 and B6 (among other metabolites) and leading to the production of S-adenosyl-L-methionine (SAM), the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. This metabolism involves three interrelated biochemical pathways: folate cycle, transsulfuration pathway and methionine cycle. These three metabolic sequences were first combined and correlated in 1964 by Laster's group [1][2][3] giving the integrated point of view of transmethylation and transsulfuration pathways, linking sulfur amino acid metabolism to the provision of methyl groups for many biochemical processes. Normal functioning of this metabolic cycle is essential for growth and development and impairment of this metabolism; transmethylation efficiency is associated with many diseases like cardiovascular diseases [4][5], liver diseases [6-9], neural tube defects [10] and brain diseases [11][12][13][14][15][16]. One-carbon metabolism alterations, low methylation and oxidative stress are all linked to Late Onset Alzheimer's Disease (LOAD) [17][18][19][20][21][22][23][24] Moreover, wide confirmed reports underline the role of SAM dependent reactions in age related neurodegeneration also showi...

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The Emerging Role of Glutathione in Alzheimer's Disease

Cited by 154 publications

References 114 publications

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

049 Physiological and molecular mechanisms associated with performance, immunometabolic status, and liver function in transition dairy cows fed rumen-protected methionine or choline

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

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