Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells

Liu, Huan; Li, Wen; Zhao, Shijing; Zhang, Xumei; Zhang, Meilin; Xiao, Yanyu; Wilson, John X.; Huang, Guowei

doi:10.1007/s00394-015-1002-2

Cited by 22 publications

(14 citation statements)

References 25 publications

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“…,b; Liu et al . ). Together with these studies, the results of our study in humans suggest that correction of disturbed homocysteine metabolism early in adult life could reduce amyloid production and eventually prevent pathological amyloid accumulation in the brain.…”

Section: Discussionmentioning

confidence: 97%

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta

Oikonomidi

Lewczuk

Kornhuber³

et al. 2016

Journal of Neurochemistry

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Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPβ, and amyloid β1-42 (Aβ1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aβ1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aβ1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 97%

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta

Oikonomidi

Lewczuk

Kornhuber³

et al. 2016

Journal of Neurochemistry

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“…Those results showed a beneficial effect from folic acid supplementation on cognitive functioning in later life [ 22 ]. It was also demonstrated that folic acid may modify Aβ accumulation in vivo [ 18 , 20 ] and in vitro [ 23 , 24 , 25 ]. In the present study, we investigated whether α-, β-, and γ-secretase are all involved the inhibition effect of folic acid on Aβ accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…One-carbon metabolism was also related to AD-like hallmarks (increased Aβ production) [ 21 , 38 ]. Previous studies have indicated that in neural cells or AD mice, folic acid supplement leads to higher availability of SAM and activities of DNA methyltransferases (DNMTs) [ 24 , 39 ], which are required for cellular methylation reactions. Therefore, altered miRNAs expression in present study may be related to the changing of methyl donor pool, along with increasing DNA methylation by folic acid administration.…”

Section: Discussionmentioning

confidence: 99%

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

Tian

Dong

et al. 2016

Nutrients

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Alzheimer’s disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component—presenilin 1 (PS1)—in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression.

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“…These authors concluded that the capacity of oAβ to modulate gene expression could generate redox and methylation-dependent epigenetic effects that contributed to the pathology of AD [144]. This prospect has been supported by a recent study [145]. Using primary hippocampal neuronal cells and HT-22 cells, as well as AD transgenic mice, Liu et al [145] investigated the influence of oAβ on DNA methylation pathway in these cells, including DNMT activity, methylation potential of cells, APP and PS1 expression, cell viability, and the methylation of respective promoters.…”

Section: Admentioning

confidence: 75%

“…Using primary hippocampal neuronal cells and HT-22 cells, as well as AD transgenic mice, Liu et al [145] investigated the influence of oAβ on DNA methylation pathway in these cells, including DNMT activity, methylation potential of cells, APP and PS1 expression, cell viability, and the methylation of respective promoters. They found that oAβ caused neuronal toxicity with lowered DNMT activity, increased APP and PS1 expression, and decreased cell viability, each consequence of which could be prevented by folic acid via methylation-dependent pathways [145].…”

Section: Admentioning

confidence: 99%

S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

et al. 2018

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S-Adenosyl methionine (SAMe), as a major methyl donor, exerts its influence on central nervous system function through cellular transmethylation pathways, including the methylation of DNA, histones, protein phosphatase 2A, and several catecholamine moieties. Based on available evidence, this review focuses on the lifelong range of severe neuropsychiatric and neurodegenerative diseases and their associated neuropathologies, which have been linked to the deficiency/load of SAMe production or/and the disturbance in transmethylation pathways. Also included in this review are the present-day applications of SAMe in the treatment in these diseases in each age group.

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Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells

Abstract: These results suggest a mechanism by which folic acid may prevent Aβ oligomer-induced neuronal toxicity.

Cited by 22 publications

References 25 publications

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

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