Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Room EM0.3211, Montreal, Quebec, H4A 3J1, Canada.
Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA.
Mol Neurobiol. 2019 Jun;56(6):4175-4191. doi: 10.1007/s12035-018-1375-3. Epub 2018 Oct 4.
Folate is an important B vitamin required for methylation reactions, nucleotide and neurotransmitter synthesis, and maintenance of homocysteine at nontoxic levels. Its metabolism is tightly linked to that of choline, a precursor to acetylcholine and membrane phospholipids. Low folate intake and genetic variants in folate metabolism, such as the methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism, have been suggested to impact brain function and increase the risk for cognitive decline and late-onset Alzheimer's disease. Our study aimed to assess the impact of genetic and nutritional disturbances in folate metabolism, and their potential interaction, on features of cognitive decline and brain biochemistry in a mouse model. Wild-type and Mthfr mice, a model for the MTHFR 677 C>T polymorphism, were fed control or folate-deficient diets from weaning until 8 and 10 months of age. We observed short-term memory impairment measured by the novel object paradigm, altered transcriptional levels of synaptic markers and epigenetic enzymes, as well as impaired choline metabolism due to the Mthfr genotype in cortex or hippocampus. We also detected changes in mRNA levels of Presenillin-1, neurotrophic factors, one-carbon metabolic and epigenetic enzymes, as well as reduced levels of S-adenosylmethionine and acetylcholine, due to the folate-deficient diet. These findings shed further insights into the mechanisms by which genetic and dietary folate metabolic disturbances increase the risk for cognitive decline and suggest that these mechanisms are distinct.
叶酸是一种重要的 B 族维生素，需要参与甲基化反应、核苷酸和神经递质的合成，以及维持同型半胱氨酸处于非毒性水平。其代谢与胆碱紧密相关，胆碱是乙酰胆碱和膜磷脂的前体。叶酸摄入不足和叶酸代谢的遗传变异，如亚甲基四氢叶酸还原酶（MTHFR）677C>T 多态性，被认为会影响大脑功能，增加认知能力下降和迟发性阿尔茨海默病的风险。我们的研究旨在评估叶酸代谢中的遗传和营养紊乱及其潜在相互作用对认知衰退和大脑生物化学特征的影响。我们使用野生型和 Mthfr 小鼠（MTHFR 677C>T 多态性模型）作为研究对象，从断奶开始至 8 个月和 10 个月龄时，分别喂食对照或叶酸缺乏饮食。我们观察到，在新物体识别范式中，Mthfr 基因型会导致短期记忆受损，突触标记物和表观遗传酶的转录水平改变，以及皮质或海马中的胆碱代谢受损。我们还发现，由于叶酸缺乏饮食，导致 Presenillin-1、神经营养因子、一碳代谢和表观遗传酶的 mRNA 水平发生变化，S-腺苷甲硫氨酸和乙酰胆碱的水平降低。这些发现进一步深入了解了遗传和饮食叶酸代谢紊乱增加认知能力下降风险的机制，并表明这些机制是不同的。
