Scroll down for key excerpt
Neurotherapeutics. 2018 Jan; 15(1): 156–175.
Published online 2018 Jan 16. doi: 10.1007/s13311-017-0593-0
PMCID: PMC5794704
PMID: 29340929
S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life
Jin Gao,1,2,3 Catherine M. Cahill,2 Xudong Huang,2 Joshua L. Roffman,1 Stefania Lamon-Fava,4 Maurizio Fava,1 David Mischoulon,1 and Jack T. Rogers2
Author information Copyright and License information Disclaimer
1Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
2Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
3Department of Clinical Psychology, Qilu Hospital of Shandong University, Qingdao, Shandong Province China
4Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA USA
Jack T. Rogers, Email: ude.dravrah.hgm@sregor.kcaj.
Corresponding author.
Go to:
Abstract
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.
Electronic supplementary material
The online version of this article (10.1007/s13311-017-0593-0) contains supplementary material, which is available to authorized users.
Keywords: S-Adenosyl-methionine, Transmethylation, Pathway, Psychiatric disease, Neurodegenerative disease
Excerpt (from full text, which is available for free):
The deficiency of SAMe may underlie the gradual hypomethylation of DNA that accompanies aging, and this hypomethylation can be alleviated by supplementation with SAMe [195]. The lower availability of SAMe may be related to the altered expression of genes involved in APP metabolism, finally producing the accumulation of Aβ peptide, contributing to the pathological processing of AD [6, 140]. DNA demethylation, when reduced by aging or nutritional deficiencies, may at least be partially avoided or restored by SAMe administration [6, 140]. In addition, BACE expression is modulated by methylation, and SAMe can restore its normal expression pattern [6]. Therefore, there have been several attempts to use SAMe nutritional supplementation in clinical trials in AD [7]. As an example of its mechanism of action, SAMe supplementation was shown to inhibit DNA demethylase, DNMT1 activity, and demethylation of PS1, a prime gene product involved in amyloidogenesis [143], as discovered in transgenic AD mice.
A further study examined whether SAMe could delay neuropathology in 3×Tg-AD mice, which harbor mutant genes for human AβPP, PS-1, and tau, here showing that SAMe supplementation in the diet did, in fact, reduce extracellular Aβ deposits [196]. SAMe treatment should therefore start early to effectively delay onset of AD symptoms. Fuso et al. [197] reported that SAMe reduced amyloid production and increased spatial memory in TgCRND8 mice. Here, SAMe inhibited the effects of B vitamin deficiency to induce PSEN1 and BACE1 expression and tau phosphorylation in TgCRND8 and wild-type mice. Certainly, SAMe treatment also reduced plaque spreading in pathways independent of B vitamin deficiency [197]. Persichilli et al. [198] reported a significant decrease of thiol levels when the B vitamin-deficient diet was supplemented with SAMe + superoxide dismutase and superoxide dismutase alone [198]. In a recent study on the APP transgenic mouse model of AD-like amyloid pathology, Do Carmo et al. [199] found that the early BACE-1 and global DNA demethylation were rescued by chronic administration of SAMe, which contributed to the reduction of amyloid pathology and the improvement in cognition function. In conclusion, these studies in AD support the rationale that it is possible to use SAMe to treat brain disorders with a plausible epigenetic mechanism. The studies are consistent with the hypothesis that SAMe administered orally is bioavailable in an active form or as an active metabolite in the brain.
