S-Adenosylhomocysteine increases β-amyloid formation in BV-2 microglial cells by increased expressions of β-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters

Lin, Herng Ching; Hsieh, Huei-Min; Chen, Yu-Hsuan; Hu, Miao‐Lin

doi:10.1016/j.neuro.2009.03.011

Cited by 55 publications

(31 citation statements)

References 31 publications

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“…The DNA methylation impairment was correlated to the site-specific demethylation of PSEN1 promoter, with consequent gene overexpression [33]. Other studies found similar results in a different cellular model [34] also suggesting the role of DNA hypomethylation in the increase of PSEN1 expression and amyloid production.…”

Section: Introductionsupporting

confidence: 59%

PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit, not the Consequence

Fuso¹,

Cavallaro

Nicolia

et al. 2012

CAR

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In recent years, in parallel with the growing awareness of the multifactorial nature of Late Onset Alzheimer's Disease, the possibility that epigenetic mechanisms could be involved in the onset and/or progression of the pathology assumed an increasingly intriguing and leading role in Alzheimer's research. Today, many scientific reports indicate the existence of an epigenetic drift during ageing, in particular in Alzheimer's subjects. At the same time, experimental evidences are provided with the aim to demonstrate the causative or consequential role of epigenetic mechanisms. Our research group was involved in the last ten years in studying DNA methylation, the main epigenetic modification, in relationship to altered one-carbon metabolism (namely high homocysteine and low B vitamins levels), in Alzheimer's experimental models. Our previous findings about the demethylation of Presenilin1 gene promoter in nutritionally-induced hyperhomocysteinemia in a transgenic mouse model clearly demonstrated that Presenilin1 is regulated by DNA methylation. One of the open questions raised by our studies was if the observed demethylation was solely due to the induced imbalance of one-carbon metabolism or could be a response to the massive deposition of amyloid plaques in transgenic mice. Here we analyzed old (10 months) mice under standard diet in order to evidence possible changes in Presenilin1 promoter methylation in transgenic (TgCRND8 mice, carrying a double-mutated human APP transgene) vs. wt mice (129Sv) after prolonged exposure to amyloid. We found no differences in Presenilin1 methylation despite a slight increase in gene expression; these results suggest that amyloid production is not responsible for Presenilin1 demethylation in TgCRND8 mice brain.

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Section: Introductionsupporting

confidence: 59%

PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit, not the Consequence

Fuso¹,

Cavallaro

Nicolia

et al. 2012

CAR

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“…These results suggested that DNMT1 played a crucial role in p53 DNA hypomethylation that caused by HHcy. SAM and SAH are important intermediates in the transmethylation process [20]. To illustrate the mechanism of HHcy-induced p53 DNA hypomethylation in ApoE 2/2 mice, the concentrations of SAM and SAH were detected by HPLC [ Fig.…”

Section: Resultsmentioning

confidence: 99%

Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE<sup>−/−</sup> mice

Ma¹,

Zhang²,

Sun³

et al. 2013

ABBS

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Hyperhomocysteinemia (HHcy) is a risk factor for cardiovascular disease and has a strong correlation with heart failure. However, the effects of HHcy on cardiac tissue remain less well understood. To elucidate the role of p53-dependent apoptosis in HHcy-induced cardiac injury, we fed ApoE 2/2 mice with high methionine diet to establish HHcy model. Serum Hcy, cardiac enzymes, and lipids were measured. The protein levels of Noxa, DNMT1, caspases-3/9, and p53 were determined by enzyme-linked immunosorbent assay. Bcl-2 and Bax proteins were detected by immunohistochemistry staining. S-adenosyl methionine and S-adenosyl homocysteine concentrations were determined by high-performance liquid chromatography. The mRNA levels of p53 and DNMT1 were analyzed by real-time polymerase chain reaction (PCR) and the methylation levels of p53 were analyzed by nested methylation-specific-PCR. Our data showed that the concentrations of serum Hcy and lipids were increased in Meth group compared with the N-control group, which indicated that the model was established successfully. The expression levels of p53 and Noxa were increased in Meth group, while the methylation status of p53 was hypomethylation. The activities of caspase-3/9 were increased in Meth group compared with the N-control group. In addition, immunohistochemistry staining showed that the expression of Bax was significantly increased in Meth and Meth-F group compared with the N-control group. In summary, HHcy induces cardiac injury by up-regulation of p53-dependent pro-apoptotic related genes Noxa and Bax, while p53 DNA hypomethylation is a key molecular mechanism in pathological process induced by HHcy.

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“…Lin and co-workers examined the hypothesis that SAH may increase the formation of the Aβ peptide in BV-2 mouse microglial cells through hypomethylation of the promoters of genes encoding presenilin 1, APP and BACE1. The results showed that SAH increases the production of A( in BV-2 cells possibly by increased expression of APP and induction of hypomethylation of APP and PSEN1 gene promoters [137]. Recent studies on murine cerebral endothelial cells have demonstrated that Aβ reduces global DNA methylation whilst increasing DNA methylation of the gene encoding neprilysin (NEP), one of the enzymes responsible for Aβ degradation, thus suppressing the NEP expression in mRNA and protein levels [138].…”

Section: Epigenetic Modifications Of Ad-related Genesmentioning

confidence: 99%

“…Studies performed in mice and in neuronal cell cultures indicate that the depletion of folate and other B vitamins, respectively from the diet or from the media, results in epigenetic modifications of AD-related genes, with a subsequent increased production of presenilin 1, BACE1, and Aβ fragments [134,136,137,139,140]. Moreover, dietary SAM administration or addiction to the media attenuated the epigenetic changes induced by B vitamin restriction [133, 141].…”

Section: Perspectivementioning

confidence: 99%

One-Carbon Metabolism and Alzheimers Disease: Focus on Epigenetics

Coppedè

2010

104

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Alzheimer’s disease (AD) represents the most common form of dementia in the elderly, characterized by progressive loss of memory and cognitive capacity severe enough to interfere with daily functioning and the quality of life. Rare, fully penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for familial forms of the disease. However, more than 90% of AD is sporadic, likely resulting from complex interactions between genetic and environmental factors. Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased plasma folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired SAM levels in AD brains. Polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with increased Hcy levels in AD individuals. Studies in rodents suggest that early life exposure to neurotoxicants or dietary restriction of folate and other B vitamins result in epigenetic modifications of AD related genes in the animal brains. Similarly, studies performed on human neuronal cell cultures revealed that folate and other B vitamins deprivation from the media resulted in epigenetic modification of the PSEN1 gene. There is also evidence of epigenetic modifications in the DNA extracted from blood and brains of AD subjects. Here I review one-carbon metabolism in AD, with emphasis on possible epigenetic consequences.

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S-Adenosylhomocysteine increases β-amyloid formation in BV-2 microglial cells by increased expressions of β-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters

Cited by 55 publications

References 31 publications

PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit, not the Consequence

PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit, not the Consequence

Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE<sup>−/−</sup> mice

One-Carbon Metabolism and Alzheimers Disease: Focus on Epigenetics

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S-Adenosylhomocysteine increases β-amyloid formation in BV-2 microglial cells by increased expressions of β-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters

Cited by 55 publications

References 31 publications

PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit, not the Consequence

PSEN1 Promoter Demethylation in Hyperhomocysteinemic TgCRND8 Mice is the Culprit, not the Consequence

Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE&lt;sup&gt;&minus;/&minus;&lt;/sup&gt; mice

One-Carbon Metabolism and Alzheimers Disease: Focus on Epigenetics

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Hyperhomocysteinemia induces cardiac injury by up-regulation of p53-dependent Noxa and Bax expression through the p53 DNA methylation in ApoE<sup>−/−</sup> mice