| Background:Alzheimer’s disease(AD)is an age-associated neurodegenerative disorder that is associated with a progressive impairment of cognition.Progressive cognitive impairment is associated with an alteration in personality and loss of bodily functions.Disability and dependence place a heavy financial burden on families and society.According to the amyloid cascade hypothesis,Aβ is the starting point for a sequence of pathophysiological events,such as senile plaque formation,tau hyperphosphorylation,neuroinflammation and cerebral amyloid angiopathy,which correlates with the degree of dementia.Although controversial,neuroinflammation in the brain has been proven to be a critical pathological hallmark of AD.The activation of peroxisome proliferator activated receptor gamma(PPAR-y)impacts the pathogenesis of AD,by reducing Aβ accumulation,inflammatory markers and the phosphorylation of tau.PPAR-γ agonists improve memory and cognition in patients with mild to moderate AD and in animal models of the condition.However,PPAR-y agonists have significant potential side effects,including fractures,heart faiture and stroke.Consequently,treatments for AD that are both safe and effective are required.Acupuncture has protective effects,however the molecular mechanisms are largely unknown.Objective:We tested the hypothesis that electroacupuncture(EA)confers therapeutic benefits through activation of PPAR-y in a rat model of AD.Methods:The male Sprague-Dawley rats were randomly divided into four groups:Control(healthy control group)(n=20),Sham(sham-operated group)(n=20),AD(untreated AD model group)(n=19)and AD+EA(AD model group treated with EA)(n=19).The AD model was induced in the latter two groups by injection of amyloid-β(Aβ)1-40 into the hippocampal CA1 area bilaterally.EA was administered at GV20 and BL23 six times per week for four weeks.Behaviour was examined using the Morris water maze test,and protein expression of beta-aloymid(Aβ),hyperphosphorylated tau protein(p-tau),PPAR-y and hyperphosphorylated p38 mitogen activated protein kinase(p38MAPK)in the hippocampal CA1 region were examined by immunohistochemistry and Western blotting.Results:1 Effect of EA on cognitive deficits1.1 All groups demonstrated a significant reduction in ELT over the five days of training(P<0.01).1.2 The AD group showed an improvement in the time taken to find the target platform during the first three days,but not thereafter.However,the AD+EA group took a significantly shorter time to find the hidden platform than the AD group(P<0.01)but not the Control and Sham groups(P>0.05).1.3 Escape latency time in the AD group was significantly increased relative to the Control and Sham groups(P<0.01 each).Furthermore,ELT in the AD+EA group was significantly attenuated compared with the untreated AD group(P<0.01).1.4 The Control and Sham group were more direct to search for the platform.While,the movement trajectory was mainly marginal and randomized in the AD group.After the electroacupuncture treatment,the motion trajectories were tend to look for the quadrant of the original platform and swam in the surrounding area.1.5 The AD group spent less time in the target quadrant than either the Control or Sham group(P<0.01 each).Moreover,Retention time was increased in the AD+EA group compared with the AD group(P<0.01).1.6 The frequency of swimming in the target quadrant was significantly increased after EA treatment,which was least in the AD group(P<0.01).2 Effect of EA on hippocampal Aβ,p-Tau Ser404 and p-Tau Thr1812.1 Immunohistochemistry:Levels of Aβ staining,indicated by the tan colouring,appeared highest,lowest and intermediate in the AD,AD+EA and Sham groups,respectively,whilst there was almost no extracellular Aβ in the hippocampal tissues of rats in the Control group(P<0.05).Subjectively,the number of p-Tau Ser404 and p-Tau Thr181 positive cells was greatest in the AD group,and least in the AD+EA group(P<0.05).2.2 Western blotting:A large quantity of Aβ protein was detected in AD and Sham animals(P>0.05).However,AD rats receiving EA stimulation demonstrated significantly lower levels of AP relative to untreated AD rats(p<0.01)The same pattern was observed for p-Tau Ser404 and p-Tau Thr181 proteins,whereby expression was highest in the AD group,and significantly decreased in AD rats undergoing EA stimulation(p<0.01).3 Effects of EA on hippocampal PPAR-γ and p-p38MAPK3.1 Immunohistochemistry:Protein expression of PPAR-y and p-p38MAPK was significantly decreased and increased,respectively,in the hippocampal CA1 region of AD rats.However,the number of PPAR-y positive cells in the AD+EA group,indicated by the tan colouring,appeared to be greater than the AD group(P<0.05).Meanwhile,the number of p-p38MAPK positive cells in the AD+EA group was subjectively less than that of the AD group,in which they appeared to be most numerous(P<0.05).3.2 Western blotting:The AD group exhibited a significant decrease in PPAR-γ protein expression relative to the Control group,which was mitigated in the AD+EA group(p<0.01).By contrast,p-p38MAPK expression was highest in the AD group and was significantly attenuated in the AD+EA group(p<0.01).Conclusions:Acupuncture at GV20 and BL23 induced neuronal protection,improved cognitive deficits and attenuated levels of Aβ and p-Tau proteins in a rat model of AD.Acupuncture at GV20 and BL23 might have a therapeutic effect on rats with AD via activation of PPAR-γ to inhibit p-p38MAPK expression. |
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