The Relationship Between Cognitive Impairment And The Expression Changes Of Drebrin, SYP And β-amyloid Protein In Brain Of An APP/PS1 Transgenic Mouse Model Of Alzheimer Disease

Alzheimer disease(AD) is a neurodegenerative disease,which clinical symptoms and neuropathological characters are more identified.The clinical symptoms of AD are progressive decrescence of memory,cognitive impairment and changes of character and behavior.Senile plaques outside neurons,neurofibrillary tangles inside neurons,selective loss of neurons and their synapses are the main neuropathological features in AD.It is believed that neuronic loss occurs mainly at advanced stage of AD,while synaptic loss occurs at earlier stage and it is more obvious at advanced stage of AD.Synaptic loss is closely correlated with cognitive impairment.Resently,many studies focus on the molecular mechanisms of synaptic loss in AD brain.The basic elements of synapse include postsynaptic element,which is dendritic spine in most case,and presynaptic element,which is the button terminal of the axon.The formation of dendritic spines is influenced by the expression and content of dendritic spine protein drebrin.Abnormal changes of dendritic spines impact on the synaptic structure and function.The expression and content of synaptophysin(SYP) often reflect the basic status of the axon terminals.It has been reported that the shape,quantity and density of dendritic spines occurred significant changes in AD brain and the expression level of dendritic spine protein drebrin,which is related with the morphlogy of dendritic spine,was significantly decreased in AD.And it also be reported that SYP usually is studied as a target of the synaptic pathological changes in AD brain,because it could reflect the synaptic structure and function.Although many studies about dendritic spine protein drebrin and synaptic protein SYP in AD brain had been documented,the relationship of the expression changs between drebrin and SYP is unknown in AD brain,and the relationship between cognitive impairment,particularly early cognitive impairment,and the expression changes of dendritic spine protein drebrin and synaptic protein SYP is not clear in AD.The progressive accumulating ofβ-amyloid protein(Aβ),as a main component of senile plaques in AD brain,is the origin and central link in pathological changes of AD and the common pathway in the occurrence and development of AD.It plays a very important role in the pathological process of AD.However,the relationship between the expression changes of dendritic spine protein drebrin and the accumulation of Aβ,which has toxic effect,is not clear.Therefore,the present study was designed to address these questions just mentioned.1.In order to understand the relationship between cognitive imparement and the expression changes of drebrin and SYP in AD,the present study examined the expression of drebrin and SYP in hippocampus by means of the Western blot in the APP/PS1 transgenic mice aged 6,9 and 12 months after the animals were tested for the ability in learning and memory by a Morris water maze.The results revealed that the expression level of drebrin in hippocampus was decreased and the ability in learning and memory was accordingly decreased in the APP/PS1 transgenic mice aged 9 months.And the decreases both the expression level of drebrin and the ability in learning and memory were more obvious in the mice aged 12 months.However,the expression level of SYP descended much later compared with the decreases of drebrin and the animal cognition.These results indicate that the role of drebrin decrease was earlier than SYP in the molecular mechanisms underlining the ethological changes at the early stage of AD,while the decrease of SYP might participate in the further development of AD.2.In order to further explore the relationship between Aβaccumulation and the expression changes of dendritic spine protein drebrin,we studied the expression of Aβand drebrin in APP/PS1 transgenic mice by using IHC,ICC,Western blot and ELISA methods in vivo and in vitro experiments.In vivo,the IHC results showed that Aβplaques appeared in cerebral cortex and hippocampal formation in APP/PS1 transgenic mice aged 6 months and Aβplaques were distributred in whole brain aged 12 months.In vitro,the ICC results showed Aβaccumulated in APP/PS1 neurons which were cultured 12 days in vitro.Aβaccumulation extended gradually from the cell body to the process with the culture days going.The ELISA results showed that the Aβexpression level in culture medium of APP/PS1 neurons was significantly increased at 12 days in vitro.It was more obvious at 18 days in vitro.The ICC results showed the punctate distribution of drebrin was rare in APP/PS1 neurons at 12 days in vitro.The Western blot results showed the protein level of drebrin was declined in APP/PS1 neurons at 12 days in vitro,and it was more obvious at 18 days in vitro.The results in vitro and in vivo experiments indicated that the progressing accumulation of Aβboth inside and outside of APP/PS1 neurons may be one of the reasons of the expression changes of dendritic spine protein drebrin.As a whole,the progressing accumulation of Aβ,which has toxic effect,both inside and outside of APP/PS1 neurons might resulted in the expression changes of dendritic spine protein drebrin,therefore,dendritic spine and synaptic structure and function were influenced,and finally cognitive impairment occurred in AD.