title: Folic acid administration inhibits amyloid β-peptide accumulation in APP/PS1 transgenic mice.
abstract: Alzheimer's disease (AD) is associated with malnutrition, altered one-carbon metabolism and increased hippocampal amyloid-β peptide (Aβ) accumulation. Aberrant DNA methylation may be an epigenetic mechanism that underlies AD pathogenesis. We hypothesized that folic acid acts through an epigenetic gene silencing mechanism to lower Aβ levels in the APP/PS1 transgenic mouse model of AD. APP/PS1 mice were fed either folate-deficient or control diets and gavaged daily with 120 μg/kg folic acid, 13.3mg/kg S-adenosylmethionine (SAM) or both. Examination of the mice after 60 days of treatment showed that serum folate concentration increased with intake of folic acid but not SAM. Folate deficiency lowered endogenous SAM concentration, whereas neither intervention altered S-adenosylhomocysteine concentration. DNA methyltransferase (DNMT) activity increased with intake of folic acid raised DNMT activity in folate-deficient mice. DNA methylation rate was stimulated by folic acid in the amyloid precursor protein (APP) promoter and in the presenilin 1 (PS1) promoter. Folate deficiency elevated hippocampal APP, PS1 and Aβ protein levels, and these rises were prevented by folic acid. In conclusion, these findings are consistent with a mechanism in which folic acid increases methylation potential and DNMT activity, modifies DNA methylation and ultimately decreases APP, PS1 and Aβ protein levels.
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Xumei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.
authors.forename: John X
authors.initials: JX
authors.lastname: Wilson
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin, China. Electronic address: huangguowei@tmu.edu.cn.
authors.forename: Guowei
authors.initials: G
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood; D005494:Folic Acid Deficiency / Q000097:blood; D020868:Gene Silencing; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood; D017422:Sequence Analysis, DNA
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; C580804:presenilin 1, mouse; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine
keywords: Alzheimer's disease; Amyloid β-peptide; DNA methylation; Folic acid; S-adenosylmethionine