The Effects And Possible Mechanisme Of Suberoylanilide Hydroxamic Acid On Cognitive Performance In Alzheimer’s Disease Transgenic Mice

Objective To observe the effects and its possible mechanism of histonedeacetylases inhibitor (HDACi) on cognitive performance in transgenic mice thatcoexpress five familial Alzheimer’s disease (FAD) mutations (5XFAD).Method Suberoylanilide hydroxamic acid (SAHA) was applied to treat5XFAD(5XFAD-CC) and wild type (WT) mice. Then the cognitive performance was assessedby Y-maze and Morris water maze. The distribution of HDAC6in the5XFAD-CCmice brain was determined by immunostaining. The protein levels of acetylatedα-tubulin, total tau and phosphorylated tau and phosphorylated glycogen synthasekinase-3β (GSK3β) were determined by Western blotting. The non-clinical safety ofdrug was also assessed in the present study.Results SAHA ameliorated learning and memory deficits in5XFAD-CC mice(t=2.642, P=0.0333for alternation; t=1.612, P>0.05for total arm entries; t=2.688,P=0.0312for total numbers of entrance in novel arm; t=3.271, P=0.017for timespenting in novel arm; F=5.936, P=0.045for hidden platform; t=2.317, P=0.049andt=2.670, P=0.0284for probe trial). Furthermore, HDAC6were expressed in thecortex and hippocampus of5XFAD-CC mice brain. Administration of SAHAsignificantly increased acetylated α-tubulin in hippocampus of WT and5XFAD-CCmice (26.42%and29.64%，respectively). Additionally, SAHA attenuated Tau-pSer396,Tau-pSer404and Tau-pThr231in hippocampus of5XFAD-CC mice (24.22%,48.98%and26.95%, respectively). Moreover, hippocampal phosphorylated GSK3β wasmarkedly reduced in SAHA-treated5XFAD-CC mice (31.29%). Lastly, chronicSAHA treatment did not show significant side-effects on the weight, blood routinetest, blood biochemical assays.Conclusion SAHA may improve cognitive performance in5XFAD-CC mice, which is associated with its significant effects on the phosphorylation of tau andGSK3β or its significant inhibitions of HDAC6. Therefore, histone deacetylaseinhibitors may provide insight into the clinical application of Alzheimer’s disease.Also, HDAC6may be a promising therapeutic target for Alzheimer’ disease.