B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice

Fuso, Andrea; Nicolia, Vincenzina; Cavallaro, Rosaria A.; Ricceri, Laura; D’Anselmi, Fabrizio; Coluccia, Pierpaolo; Calamandrei, Gemma; Scarpa, Sigfrido

doi:10.1016/j.mcn.2007.12.018

Cited by 182 publications

(175 citation statements)

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“…The expression of BACE, as well as PS1, increased after the reduction of folate and vitamin B12 in the culture medium, with a consequent increase in Aβ production [14]. Another study published by the same group showed similar results when evaluating the effect of vitamin B deficiency in an animal model of AD [34]. Because an increase in SAM concentration is a known effect of a methionine-supplemented diet [35], which in turn could alter the availability of methyl groups, we expected a decrease in gene expression due hypermethylation.…”

Section: Discussionmentioning

confidence: 65%

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

Silva¹

2014

J Nutr Food Sci

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Sciencesda Silva et al., J Nutr Food Sci 2013, 4:1 http://dx.doi.org/10.4172/2155-9600.1000253 *Corresponding author: Vânia D'Almeida, R. Napoleão de Barros, nº 925, 3º andar, São Paulo-SP, Brazil, CEP: 04024-002, Brazil, Tel: 55-11-21490155; Fax: 55-11-55725092; E-mail: vaniadalmeida@uol.com AbstractMaternal hyperhomocysteinemia (hHcy) induced by a high methionine diet delays brain maturation and leads to impairment of learning performance in the offspring. Because methionine-homocysteine metabolism is related to the regulation of gene expression through one-carbon metabolism, we investigated whether maternal supplementation with methionine affects the expression of Adam10, Bace1, Bace2, Ps1, Ps2, Tace, App, and Tnf-α, genes related to Alzheimer's disease (AD) risk, in the offspring. Thirteen female mice were distributed into the following groups: a) standard diet and b) standard diet supplemented with 1% methionine in water. After birth, the offspring were organized into Control (CT) and Supplemented Diet (SD) groups, and at Postnatal Day (PND) 90, all animals were weighed and then euthanized. The homocysteine (Hcy) concentration in plasma was measured, and the whole brain was weighed and dissected, and the hippocampus used for gene expression analyses. A decrease in total body weight was found in SD group, but no differences in brain weight were observed. The maternal diet did not seem to affect the Hcy concentration of PND 90 offspring. No differences were found in the expression of AD related genes in the hippocampus (p>0.05). In conclusion, hHcy induced by methionine supplementation during pregnancy and lactation did not affect the expression of genes related to AD risk in the offspring.

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Section: Discussionmentioning

confidence: 65%

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

Silva¹

2014

J Nutr Food Sci

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“…The impairment of either remethylation or transsulfuration pathways induced by B vitamin deficiency can lead to hyperhomocysteinemia, alteration of GSH metabolism and increase of SAH levels. Being SAH a strong competitive inhibitor of SAM-dependent methyltransferases, involved in methylation of DNA (among others substrates) and gene expression regulation, SAH accumulation can induce hypomethylation, by decreasing SAM/SAH ratio (methylation potential; MP), and deregulation of gene expression [46][47]. Furthermore, the alteration of GSH metabolism derived from transsulfuration pathway impairment suggests that hypomethylation, together with the alteration of the redox homeostasis, is a mechanism through which one-carbon metabolism alteration is involved in brain diseases [46,[48][49].…”

Section: Sam Metabolismmentioning

confidence: 99%

“…The importance of methylations for normal brain functions is well known. It has been recently shown that alteration of one-carbon metabolism regulates expression of two key enzymes in the amyloid pathway: β-secretase (BACE1) and presenilin (PSEN1), such that low methylation potential is associated with increased Aβ production [47,[95][96]. Furthermore, activation of protein phosphatase 2A (PP2A) is SAM-dependent, and disturbed methylation status is associated with increased phosphorylation of tau, another phenomenon strictly implicated in the pathogenesis of AD [97][98].…”

Section: Involvement Of Sam In Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

“…To study the efficacy of SAM in contrasting one-carbon metabolism alterations in neurodegeneration, Fuso and coworkers studied the pathogenic role of hyperhomocysteinemia induced by diet deficient of B vitamins (folate, B12, and B6), using transgenic TgCRND8 mice overexpressing mutated human APP gene and showing early and age-related Aβ plaque deposition [47]. The pathogenetic model was designed to reproduce, as much as possible, one-carbon metabolism alterations caused by B vitamin deficiency, inducing exacerbation of AD-like features in TgCRND8 AD mice.…”

Section: Involvement Of Sam In Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

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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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“…DNA methylation appears to play a role in human cognitive function, since mutations affecting the methylation machinery (DNMT3b) and proteins that bind to methylated DNA (MeCP2), have been shown to cause ID (20,21). Defects in DNA methylation are also thought to play a role in neurodegeneration in Alzheimer's disease, due to Alzheimer's-associated defects in the metabolism of methyl-donor molecules (22)(23)(24).…”

Section: Dna Methylation and The Formation Of Long Term And Distant Mmentioning

confidence: 99%

Epigenetic regulation of memory: implications in human cognitive disorders

Kramer

2013

BioMolecular Concepts

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Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders.

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B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice

Cited by 182 publications

References 54 publications

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

Hyperhomocysteinemia and Gestational Programming of Genes Involved in Alzheimer’s Disease Pathogenesis

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

Epigenetic regulation of memory: implications in human cognitive disorders

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