Disturbed deoxythymidine triphosphate biosynthesis due to the inhibition of thymidylate synthase (TS) can lead to uracil accumulation in DNA, eventually, lead to neurocytes apoptosis and cognitive decline. Folic acid supplementation delayed cognitive decline and neurodegeneration in senescence-accelerated mouse prone 8 (SAMP8). Whether folic acid, one of nutrition factor, the effect on the expression of TS is unknown. The study aimed to determine if folic acid supplementation could alleviate age-related cognitive decline and apoptosis of neurocytes by increasing TS expression in SAMP8 mice. According to folic acid concentration in diet, four-month-old male SAMP8 mice were randomly divided into three different diet groups by baseline body weight in equal numbers. Moreover, to evaluate the role of TS, a TS inhibitor was injected intraperitoneal. Cognitive test, apoptosis rates of neurocytes, expression of TS, relative uracil level in telomere, and telomere length in brain tissue were detected. The results showed that folic acid supplementation decreased deoxyuridine monophosphate accumulation, uracil misincorporation in telomere, alleviated telomere length shorting, increased expression of TS, then decreased apoptosis rates of neurocytes, and alleviated cognitive performance in SAMP8 mice. Moreover, at the same concentration of folic acid, TS inhibitor raltitrexed increased deoxyuridine monophosphate accumulation, uracil misincorporation in telomere, and exacerbated telomere length shorting, decreased expression of TS, then increased apoptosis rates of neurocytes, and decreased cognitive performance in SAMP8 mice. In conclusion, folic acid supplementation alleviated age-related cognitive decline and inhibited apoptosis of neurocytes by increasing TS expression in SAMP8 mice.

由于胸苷酸合酶 (TS) 的抑制，脱氧胸苷三磷酸生物合成受到干扰，可导致尿嘧啶在 DNA 中积累，最终导致神经细胞凋亡和认知能力下降。补充叶酸可延缓衰老加速小鼠 pron 8 (SAMP8) 的认知衰退和神经退行性变。营养因子之一叶酸是否对TS表达有影响尚不清楚。该研究旨在确定补充叶酸是否可以通过增加 SAMP8 小鼠的 TS 表达来缓解与年龄相关的认知衰退和神经细胞凋亡。根据饮食中叶酸浓度，将4月龄雄性SAMP8小鼠按基线体重随机分为3个不同饮食组，数量相等。此外，为了评估 TS 的作用，腹膜内注射 TS 抑制剂。检测认知测试、神经细胞凋亡率、TS表达、端粒相对尿嘧啶水平、脑组织端粒长度。结果表明，补充叶酸可减少脱氧尿苷单磷酸的积累、端粒中尿嘧啶的错误掺入，减轻端粒长度缩短，增加TS的表达，然后降低神经细胞的凋亡率，并减轻SAMP8小鼠的认知能力。此外，在相同浓度的叶酸下，TS抑制剂雷替曲塞增加了SAMP8小鼠脱氧尿苷单磷酸的积累、端粒中尿嘧啶的错掺，加剧了端粒长度的缩短，降低了TS的表达，进而增加了神经细胞的凋亡率，降低了SAMP8小鼠的认知能力。总之，补充叶酸可通过增加 SAMP8 小鼠的 TS 表达来缓解与年龄相关的认知衰退并抑制神经细胞凋亡。