ABSTRACT
Objective To observe the effects of histone deacetylases inhibitor (HDACi) on cognitive performance and cerebral tau phosphorylation in transgenic mice coexpressed five familial Alzheimer' s disease mutations (5XFAD).Method The total 12 5XFAD-CC and 12 wild type (WT) mice were administrated with suberoylanilide hydroxamic acid ( SAHA,n =7) and vehicle ( n =5 ),respectively.The cognitive performance was assessed by Y-maze and Morris water maze.The protein levels of acetylated α-tubulin,total tau and phosphorylated tau and phosphorylated glycogen synthase kinase-3β (GSK3β) were determined by Western blotting.Results SAHA ameliorated learning and memory deficits in 5XFAD-CC mice (39.10％ ±2.25％,t =2.688,P =0.0312 for total numbers of entrance in novel arm; 26.81％ ±0.78％,t =3.271,P =0.017 for time spending in novel arm; F =5.936,P =0.045 for hidden platform;31.70％ ±4.21％,t =2.317,P =0.049 for probe trial).Administration of SAHA significantly increased acetylated α-tubulin in hippocampus of WT and 5XFAD-CC mice (26.42％ and 29.64％,respectively).Additionally,SAHA attenuated tau-pSer396,tau-pSer404 and tau-pThrThr231 in hippocampus of 5XFAD-CC mice (24.22％,48.98％ and 26.95％,respectively). Moreover,hippocampal phosphorylated GSK3β was markedly reduced in SAHA-treated 5XFAD-CC mice (31.29％). Conclusion SAHA may improve cognitive performance in 5XFAD-CC mice, which is associated with its significant effects on the phosphorylation of tau and GSK3β.
ABSTRACT
Objective To explore whether ginsenoside Rg1 can attenuate ?-amyloid peptide 25-35-induced Tau hyperphosporylation in rat embryo cortical neurons by regulating the activity of GSK-3? and PP2A. Methods Primary cultures of cortical neurons were prepared from the embryonic day 18?2 in Sprague-Dawley rats. The experimental groups were designed as follows:1.Neurons culture (control group); 2. Neurons exposed to 20?mol/L A?_ 25-35 for 12 hours (A?-model group); 3.Neurons exposed to 20?mol/L A?_ 25-35 and 10 mmol/L lithium chloride (LiCl), a specific inhibitor of glycogen synthase kinase-3?(GSK-3?), for 12 hours (LiCl group); 4.Neurons exposed to 20?mol/L A?_ 25-35 for 12 hours in the presence of 24-hour pretreatment with ginsenoside Rg1 (Rg1 pretreatment group) . Western blotting and immunocytochemical staining were used to detect the levels of Tau phosphorylation,total Tau and GSK-3? in cortical neurons. Non-radioimmunoassay was introduced to detect the activity of protein phosphatase 2A (PP2A). Results In A?-model group, the levels of Tau protein phosphorylation in the sites of Ser 396 ,Ser 199/202 ,Thr 231 and total Tau were enhanced. Meanwhile, the expression of GSK-3? was also increased, but the activity of PP2A was unchanged. In LiCl group and Rg1 pretreatment group , the hyperposphorylations of Tau protein and total Tau and the expression of GSK-3? were markedly reduced compared to those of the A?-model group (P