| ObjectiveWith the aging of society,AD has become an increasingly obvious age-related degenerative encephalopathy.Although AD has been studied for more than 100 years and great progress has been made,prevention strategies still face many challenges.The main neuropathological changes in AD are the abnormal expression,processing and co-deposition of proteins.To a minimum,the co-deposition of two proteins A? and tau,which are manifested as the basic pathological changes in AD,is still unclear.However,the influence of synapses on cognition cannot be ignored in the basic pathological changes of AD.Besides the synaptic structure and structural proteins,the functional protein ?7-nAchRs interacts with mGluR(In the central nervous system,?7-nAchRs is involved in maintaining the homeostasis and synaptic plasticity of the nervous system.mGluR is an important glutamate receptor in the central nervous system,which is involved in maintaining neuron survival,synaptic plasticity and neural circuit formation)plays a key role in the occurrence and development of AD.Traditional Chinese medicine plays an indispensable role in the fight against AD.GAPT is an anti-AD Chinese herbal compound preparation,which is composed of drugs for tonifying kidney,resolving phlegm,invigorating qi and activating blood.Based on the previous work,this research will discuss the effect of ?7-nAchRs and mGluR interaction on the improvement of the cognition of AD mice,to explore the improvement of cognition of sporadic AD mice induced by traditional Chinese medicine GAPT,and to elucidate the early neuroprotective mechanism of GAPT.Method120 C57/BL6 J mice were randomly divided into 20 mice in normal group(0.5%CMC)and 100 mice in the other groups.The other 100 mice were injected with Streptozotocin(STZ)3mg/kg(5?l)in bilateral lateral ventricles(0.8mm behind the anterior fontanelle and 1.5mm beside the sagittal suture)on day 1 and day 3.Those mice were randomly divided into model group(0.5%CMC),donepezil group(0.92mg/kg soluble in 0.5%CMC),GAPT high-dose group(20mg/kg soluble in 0.5%CMC),GAPT medium-dose group(10mg/kg soluble in 0.5%CMC),and GAPT low-dose group(5mg/kg soluble in 0.5%CMC),with 20 mice in each group.The mice were given a continuous gavage for three months.Behavior tests(Morris water maze and platform)were used to observe the learning ability and memory retention ability of mice.Ultrastructural changes of synapses in mice were observed under transmission electron microscope.The expression and distribution of ?7-nAchR,mGluR5,PSD95 and Shank1 were observed by immunohistochemistry and Western-blot method.Result1.Morris water maze results showed that GAPT could reduce the swimming distance and latency of AD mice in directional navigation.The incubation period of the jumping test was increased,which showed that the learning ability and memory retention ability of the mice could be improved by the GAPT.2.The results of electron microscopy showed that the appearance of synapses in the model group was fuzzy,and the structure was destroyed.Mitochondria within the synapse are fuzzy with cristae rupture.Compared with the model group,the synaptic morphology and structure of each intervention group were normal,and the synaptic cleft was clear and normal.3.Western blot and immunohistochemical staining results showed that the expression and distribution of model group ?7-nAchRs,mGluR5,PSD95 and Shank1 were significantly decreased compared with the normal group(P<0.01),the expression and distribution of model group mGluR5 were significantly increased compared with the normal group(P<0.01 or P<0.05).Compared with the model group,the expression and distribution of ?7-nAchRs,mGluR5,PSD95 and Shank1 in each intervention group were improved to varying degrees(P<0.01 or P<0.05),suggesting that this may be related to the neuroprotective mechanism of GAPT.ConclusionAfter 3 months of continuous intragastric administration of the compound Chinese medicine GAPT,GAPT can improve spatial learning ability and memory retention ability,the ultrastructure of neurons and synapses,and the expression and distribution of PSD95 and Shank1 on the hippocampus in AD mice,so as to make the connections between synaptic structures closer and improve the plasticity of synapses.Compound TCM GAPT can also improve the expression of presynaptic membrane functional protein?7-nAchRs and postsynaptic membrane functional protein mGluR5.Activation of ?7-nAchRs can promote the depolarization of presynaptic membrane and release neurotransmitters,which combine with mGluR5 to improve synaptic transmission.Therefore,the improvement of the learning and memory ability of sporadic AD mice by GAPT may be related to the improvement of synaptic structure and function.This will provide a new experimental basis for the treatment and clinical medication of AD. |
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