Abstract: Objective To explore the preventive effects of 5-methyltetrahydrofolate(5-MTHF)on D-galactose(D-gal)and aluminum chloride(AlCl₃)induced cognitive decline in Alzheimers disease(AD)rats. Methods A total of 40 male Wistar rats were divided into control group, model group, low-5-MTHF group and high-5-MTHF group according to body weight, with 10 rats in each group. The model group was given intraperitoneal injection of 60 mg/kg BWD-gal and 10 mg/kg BW AlCl₃, and intragastric administration of physiological saline for 6 weeks. The low and high 5-MTHF groups were given intraperitoneal injection of 60 mg/kg BW D-gal and 10 mg/kg BW AlCl₃, and intragastric administration of 1 mg/kg BW(low-5-MTHF group)or 5 mg/kg BW(high-5-MTHF group)for 6 weeks. The learning and memory function of rats were evaluated with Morris water maze. The processing of amyloid precursor protein(APP)was evaluated with the content of β-amyloid protein 1-42(Aβ_1-42)and phosphorylated Tau protein(p-Tau), mRNA expression of disintegrin and metallopeptidase domain 10(ADAM10), and β-site amyloid precursor protein cleaving enzyme 1(BACE1). The cholinergic function was determined with the activity of acetylcholinesterase(AChE), oxidative stress was determined with superoxide dismutase(SOD)and malondialdehyde(MDA), and endothelial cell function was determined with cytokines. Results The water maze results showed that the escape latency of each group gradually decreased with the increase of training time(F_day=67.37, P<0.001; F_group=6.36, P=0.001). Moreover, there was an interaction between group and day factors in escape latency(F_{day x group}=2.72, P=0.007). Compared with the control group, the model group had longer escape latency, increased contents of Aβ_1-42 and p-Tau in the brain, higher activites of serum AChE and nitric oxide synthase(NOS), higher levels of tumor necrosis factor-α(TNF-α), endothelin-1(ET-1), MDA and interleukin-6(IL-6)and higher BACE1 mRNA expression in the hippocampus(P<0.05), but decreased activity of serum SOD and lower ADAM10 mRNA expression in the hippocampus(P<0.05), suggesting the success of AD modeling. Compared with the model group, the low-5-MTHF group had larger numbers of crossing the platform, longer time spent in the target quadrant, higher activity of serum SOD and higher ADAM10 mRNA expression in the hippocampus(P<0.05), but shorter escape latency, lower content of serum IL-6 and reduced BACE1 mRNA expression(P<0.05). Compared with the model group, the high-5-MTHF group had shorter escape latency, lower content of Aβ_1-42 in the brain, lower concentrations of serum nitric oxide(NO)and TNF-α(P<0.05). Moreover, the mRNA expression of ADAM10 between the 5-MTHF groups were dose-dependent(P=0.016). Conclusion 5-MTHF can prevent D-gal and AlCl₃ induced cognitive decline in AD rats. The underlying mechanism may be achieved via regulating APP processing and endothelial cell secretion and repressing oxidative stress.

Key words: 5-methyltetrahydrofolate, D-galactose, Alzheimers disease, Aluminum chloride, Rat