Of PNS, Jasminoidin Its Compatibility On APP / PS1 Mice Dendritic Spine Injury In Rats And Its Mechanism

1. BackgroundAlzheimer’s disease (AD) is one of the most common and lethal neurodegenerative disorders characterized by progressive cognitive decline, memory impairment, and changes in behavior and personality, with rising incidence among elderly people. One of the pathological hallmarks of AD is progressive loss of neurons and synapses in the cerebral cortex and hippocampus. Another hallmark of AD is senile plaque (SP), composed of Amyloid β(Aβ) Meanwhile another distinctive features of AD is neurofibrillary tangles (NFTs), composed of bundles of paired helical filaments, mainly containing hyperphosphorylated microtubule-associated tau protein. Synaptic function and neuronal loss are the earliest clinical sign of AD, and such alteration is thought to be responsible for cognitive deficits. Dendritic spines are tiny protrusions along dendrites, which constitute major postsynaptic sites for excitatory synaptic transmission, was the base of learning and memory. The progressive loss of spine density and the degeneration of dendrite have been detected in AD patients.2. ObjectiveBased on our previous experiments, GP and PNS, the active ingredient of gardenia and Panax notoginseng, could across the blood-brain barrier to play an important role. In vitro experiment, we found that the compound of PNS and GP has the effect of promoting axon growth damaged by amyloid, demonstrated by greater total length of neurites. In vivo esperiment, our preliminary data have showed that the combination of GP and PNS could drastically improve the learning and memory ability of the amyloid injection group in Y maze test. Furthermore, the combination of GP and PNS could improve learning and memory ability of AD transgenetic mice modle in the water maze test. Meanwhile, the combination of GP and PNS could increase the density of dendritic spines of hippocampal CA1area in APP/PS1mice on prophylactic use of drug. So this project focus on dendritic spine related to learning and memory, exploring the mechanism of the combination of GP and PNS in reconstruction of neuron synaptic structure and function.3. Materials and Methods4-month-old APP/PS1double transgenic mice were randomly divided into5groups, the transgenic modle group (Tg), the combination of GP and PNS group, GP group, PNS group, Aricept group were used as positive drug group. The wild-type littermates were used as controls. After3month administration of drugs, Glogi staining was applied to observe the effect on the lengh and density of dendritic spine in hippocampal CA1pyramidal cells. Immunohistochemistry was used to detect drug’s effect on AMPA(GluRl) in postsynaptic membrane density. Western blot was used to measure the level of PSD-95, drebrin and GAP-43. PSD-95and drebrin are related to spine morpholopy and spine density.4. Results4.1The change of dendritic spine in hippocample CA1pyramidal cellsCompared with7-month-old WT group, the complexity and the lengh of dendritic hippocample CA1pyramidal cells in Tg group were decreased. Meanwhile the spine density of apical and basal was remarkable decreased too, especially in the mature spine. Compared with Tg group, PNS, PNS+GP and Aricept significantly increase the complexity and the lengh of dendritic. PNS, GP and Aricept have significantly increase apical and basal spine density of hippocample CA1pyramidal cells. What is more interesting is that GP is more effective in increasing the spine density. So it seemed that the drugs played a role in pathological changes of dendritic spine loss in APP/PS1transgenic mice.4.2Drug’s effect on GluR1Compared with7-month-old WT group, immunohistochemical result showed that there was no difference in the positive cell density of GluRl on hippocample CA1pyramidal cells. Meanwhile, no difference was found between Tg group and drug treatment group.4.3Drug’s effect on spine associated proteinWestern Blot results showed that the Tg group’s cortex and hippocampus level of PSD-95was significant lower than WT group. But there is no difference in the level of PSD-95between drug treatment group and Tg group. However, PNS and PNS+GP could significant increase the level of PSD-95in cortex. Although no difference was found in the expression level of Drebrin and GAP-43in the hippocampus, PNS and GP shows more significant effective on increasing the level of Drebrin in cortex.4.4The correlation between synaptic plasticity and Morris water mazeThe complexity and the lengh of dendritic hippocample CA1pyramidal cells were negatively and linearly correlated with distance travelled in morris water maze.5ConclusionPNS and GP has the effect of improving the lost of dendritic spines of APP/PS1transgenic mice. Compound of PNS and GP has effective on increasing the level of proteins which relate to dendritic spine in cortex.