| Background and Objective With the extension of life expectancy and aging population structure, the Alzheimer's disease(AD), an age-related progressive neurodegenerative disease,characterized progressive memory loss and decline of cognitive function, has been the most common type of dementia. The effective treatment of AD has been a major challenge on account of its poor elucidated pathogenesis. Recent studies have found AD is a kind of epigenetic disease and epigenetic-based therapies of AD have become a hot topic. Curcumin, an inhibitor of p300 histone acetylase, probably related to alleviate A? deposition. However, this specific epigenetic mechanism has never been investigated for the treatment of AD with curcumin. Therefore, the aim of the present study was to explore the influence of histone acetylase p300 on the cognitive function of AD rat with curcumin administration.Materials and methods With stable escape latency selected by Morris water maze, 45 male Wistar rats were randomly divided into the control group, the AD model group and the curcumin administration group. Combined D-galactose intraperitoneal injection and A?25-35 hippocampus stereotactic injection, the AD rat models were established. The administration group rats were injected by intraperitoneal with curcumin, which dissolved in DMSO and 0.9%Na Cl to the concentration of 50mg/ml. And the dose of curcumin was determined according to their weight(200mg/kg). 28 days after treatment, 9 rats of each group were randomly selected to test the spatial learning and memory by Morris water maze. Hippocampus morphology structure was observed by Optical microscope after haematoxylin and eosindye(HE) staining. 6 rats in every group were extracted CSF from the cistern through the foramen magnum using l ml syringe. Enzyme-linked immunosorbent assay(ELISA) was used to detect A?1-42 and tau concentration of CSF; the expression of APP and tau protein was observed by immunohistochemical; the expression of acetylated histone H3 was detected by Western blot; histone acetylase activity was detected by ELISA; m RNA levels of p300, APP, BACE1 were evaluated by real-time quantitative PCR.Results1. Curcumin improved the cognitive function disorder of AD rats Compared with the control group rats, the average escape latency(AEL) of AD model group rats was significantly longer(P<0.05 or P<0.01), time in the quadrant?of that was shorter(P<0.01), the crossing number of that was less(P<0.01);Compared with AD model group rats, the AEL of administration group rats was significantly shorter(P<0.05 or P<0.01), time in the quadrant of that was longer(P<0.01), the crossing number of that was more(P<0.05).2. Curcumin attenuated the pathological damages of the hippocampus in AD rats Compared with the control group rats, AD model group rats emerged a severe damage in hippocampus such as nuclear contraction, perivascular space broadening and cell edema, observed in CA3 and dentate gyrus(DG) region. 28 d after treatment,Curcumin obviously improved the hippocampus injuries compared with AD model group rats.3. Curcumin reduced the expression of APP and tau protein in the AD rats hippocampus Compared with the control group rats, the expression of APP and tau protein in AD group rats was enhanced(P<0.01); compared with AD group rats, the expression of APP and tau protein in the administration group rats was attenuated(P<0.05 or P<0.01).4. Curcumin reversed the A?1-42 and tau concentration of CSF in AD rats Compared with the control group rats, the A?1-42 concentration of CSF in AD group rats was significantly lower(P<0.01), and tau concentration of that was obviously higher(P<0.01). Compared with AD group rats, the A?1-42 concentration of CSF in the administration group rats was notably higher(P<0.01), and tau protein of that was distinctly lower(P<0.01).5. Curcumin suppressed acetylation of histone H3 and HAT activity in the hippocampus of AD rats Compared with the control group rats, the expression of histone H3 acetylation and the activity of HAT were elevated in the hippocampus of AD rats(p<0.01). 28 d after administration, curcumin reversed the enhanced expression of histone H3 acetylation and HAT activity of AD group rats(p<0.01).6. Curcumin reduced the m RNA levels of p300, APP and BACE1 in the hippocampus of AD rats Compared with the control group rats, the m RNA levels of p300, APP, BACE1 were increased in the hippocampus of AD rats(p<0.01). After treatment with curcumin, the m RNA levels of p300, APP, BACE1 were decreased compared with AD rats(p<0.01).Conclusions28 consecutive days treatment significantly reversed D-galactose and A?25-35-induced spatial memory disorder, the histopathological damage changes and the expression of APP and tau in hippocampus of AD rats. In addition, curcumin attenuated the HAT activity and the m RNA level of p300, and the expression of acety-Histone H3. Meanwhile, the m RNA level of BACE and APP were detected to reduce. These results suggested curcumin may improve congnitive function of AD via inhibiting p300 HAT to its target gene expression of BACE1 and APP. |
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