Folic acid and S-adenosylmethionine reverse Homocysteine-induced Alzheimer's disease-like pathological changes in rat hippocampus by modulating PS1 and PP2A methylation levels

Background: Abnormally elevated homocysteine (Hcy) is recognized as a biomarker and risk factor for Alzheimer's disease (AD). However, the underlying mechanisms by which Hcy affects AD are still unclear. Objectives: This study aimed to elucidate the effects and mechanisms by which Hcy affects AD-like pathological changes in the hippocampus through in vivo and in vitro experiments, and to investigate whether folic acid (FA) and S-adenosylmethionine (SAM) supplementation could improve neurodegenerative injuries. Methods: In vitro experiments hippocampal neurons of rat were treated with Hcy, FA or SAM for 24 h; while the hyperhomocysteinemia (HHcy) in Wistar rats was established by intraperitoneal injection of Hcy, and FA was added to feed. The expression of beta-amyloid (A beta), phosphorylated tau protein, presenilin 1 (PS1) at the protein level and the activity of protein phosphatase 2A (PP2A) were detected, the immunopositive cells for A beta and phosphorylated tau protein in the rat hippocampus were also evaluated by immunohistochemical staining. Results: FA and SAM significantly repressed Hcy-induced AD-like pathological changes in the hippocampus, including the increased tau protein phosphorylation at Ser214, Ser396 and the expression of A beta 42. In addition, Hcy-induced PS1 expression increased at the protein level and PP2A activity decreased, while FA and SAM were able to retard that. Conclusions: The increase in PS1 expression and decrease in PP2A activity may be the mechanisms underlying the Hcy-induced AD-like pathology. FA and SAM significantly repressed the Hcy-induced neurodegenerative injury by modulating PS1 and PP2A methylation levels.