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The Primary Study on the Relationship between Central VGLUT1 Expression and the Function of Learning and Memory

Author: ZhaoYueYing
Tutor: ZhangYongXiang；ZhouWenXia
School: PLA Military Academy of Medical Sciences
Course: Pharmacology
Keywords: Rapid aging model mice I type vesicle glutamate transporter Amyloid precursor protein Gene Expression Protein expression Learning and memory function Puzzle drugs
CLC: R749.1
Type: Master's thesis
Year: 2007
Downloads: 138
Quote: 0
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Abstract

Alzheimer's disease (Alzheimer's disease, AD) in cognitive dysfunction in neurodegenerative diseases, mainly due to the complexity of its pathogenesis, combined with the reversal of the pathological changes in brain formation is very difficult, therefore, to the clinical treatment and The prevention and treatment the AD of drug research and development has brought a great deal of difficulty, so far there is no ideal therapy advent. AD is a polygenic complex diseases, multiple genes and their expression products has an important regulatory role in the central cognitive dysfunction in the pathophysiological process. Therefore, the study to clarify the function of these important regulatory genes are of great significance for revealing the pathogenesis of AD as well as the prevention and treatment of AD drug target discovery and research. Vesicle glutamate transporter (Vesicular glutamate transporter, VGLUT) the vesicle glutamate neurons neurotransmitter transporter, there are three types were identified. Which VGLUT1 in neurons rich region, such as the cerebral cortex and hippocampus, expression, and selectively at excitatory glutamatergic neuronal processes synaptic vesicles on the end, responsible for the extracellular glutamate transported into the vesicles synaptic vesicles and regulate excitatory neurotransmitter release and subsequent physiological processes important functions in synaptic glutamatergic neurons and their axons end of a highly specific marker. VGLUT1 expression levels change in the effectiveness of the glutamate synaptic transmission has an important influence its expression levels reflect the number of glutamatergic neurons and their synapses, activity and functional status. However, the of VGLUT1 expression of learning and memory function relationships is not very clear. Four weeks of the room in the early study found that, given a 12-month-old senescence accelerated mouse SAMP8 continuous oral huperzine A and Liu Wei Di Di Huang Tang, the hippocampus VGLUT1 expression change significantly, suggesting that AD therapy huperzine puzzle role of Chinese herbal formula Liu Wei Di Huang Tang on the learning and memory function and regulation of hippocampal VGLUT1 expression has a certain relationship. Rapid aging subline of senescence accelerated mouse (senescence-accelerated mouse, SAM) SAM-prone / 8, SAMP8) typical characteristics with increasing age presents learning and memory dysfunction, brain neuron loss, Aβ deposition and the like abnormal AD pathological changes and the expression of many genes, is a good model of AD research in gene and protein level. Reveal VGLUT1 learning and memory function, explore as the prevention and treatment of AD drug screening targets the possibility of accumulation of experimental evidence, and follow-up studies, this study SAMP8 model, using real-time quantitative PCR and Western-blot and immunohistochemistry technology, first observed the the SAMP8 aging process in hippocampal and cortical VGLUT1 expression and distribution changes, in order to investigate the variation of expression in the process of learning and memory function recession; then shuttle box experiment, observed VGLUT1 expression with mice in Conditional evasive reaction experimental process of learning and memory to obtain the relationship; on this basis, observed the good effect of the AD patients or model animals, but different function attending Chinese medicine compound Liuwei ground yellow soup (LW), Ba Wei Di Huang Tang ( BW), Huanglianjiedu-soup (HL), Spherical party (TXF) and Angelica and Peony Powder (DSS), as well as for the treatment of AD clinical drug huperzine of the VGLUT1 gene and protein expression, and to explore its prevention and treatment of AD drug reaction. Rapid aging hippocampal and cortical VGLUT1 expression and distribution changes during the aging process of the model mice SAMP8 typical feature of cognitive function were age-recession, in order to reveal VGLUT1 is associated with the increase in age-related cognitive decline, this study using real-time quantitative PCR and Western-blot and immunohistochemical techniques, observed SAMP8 hippocampus and cortical VGLUT1 gene and protein expression changes in the aging process and distribution. 1. APP expression APP senile plaques major components of AD patients brain Aβ precursor protein, there are a large number of studies have shown that APP transgenic mice showed significant learning and memory dysfunction, SAMP8 aging process in brain APP gene and protein expression and beta amyloid deposition gradually increased. Therefore, this study to APP expressed as a control, the first observation of SAMP8 in the process of aging in the hippocampus and cortex of APP gene and protein expression changes. The results showed that the SAMR1 the hippocampus and cortex APP gene and protein expression with increasing age did not change significantly SAMP8 hippocampus and cortex of APP gene and protein expression gradually increased with increasing age; SAMR1 compared with the same months of age, APP gene and protein 2-month-old SAMP8 hippocampus and cortex were unchanged, but its expression at 6 and 12 months of age were significantly higher than those of SAMR1 control group. 2. VGLUT1 expression and changes in the distribution of the results of this study show that increase as the month the SAMR1 hippocampal and cortical VGLUT1 the gene and protein expression did not change significantly. SAMP8 hippocampus and cortical VGLUT1 expression showing the SAMR1 different variation, the performance for the first and then decreased, showing the \That at 2 months of age compared to their expression with age SAMR1 no significant change in expression was significantly lower than the 2-month-old age SAMR1 6 months, 12 months old expression restored to nearly 2-month-old level, and with peers SAMR1 There was no significant difference. The immunohistochemical observation results show that, VGLUT1 is mainly present in the cortex, the cytoplasmic membrane of hippocampal neurons, the distribution of the hippocampus dentate gyrus more. The VGLUT1 gene and protein expression in SAMR1 and SAMP8 hippocampus and cortex with aging in the change in the law is the same, namely SAMR1 in hippocampal and cortical VGLUT1 distribution did not change significantly with increasing age; SAMP8 at 2 months of age, the expression of phase with peers SAMR1 ratio did not change significantly at 6 months of age was significantly lower than the 2-month-old age SAMR1 expression restored 12 months to nearly 2 months of age, there is no obvious difference compared with the same age SAMR1. , VGLUT1 expression in mouse relationship between learning and memory in the application for further study of the relationship of the of VGLUT1 expression of learning and memory function, this study reflect the animal conditioned avoidance response learning memory capacity shuttle box experiment, observed VGLUT1 expression with mice learning MEMORY. The experiment used male mice, and Experiment 6 consecutive days. At the end of the sixth day of the experiment, divided into six groups according to the academic pros and cons, and not learning behavior of laboratory mice as controls. Then observe the changes in the hippocampus and cortex of APP and VGLUT1 gene and protein expression, and to investigate the of VGLUT1 expression of learning and memory obtained relationship. The experimental results show that, compared with the control group, the hippocampus and cortical VGLUT1 gene and protein expression in volume with learning and memory scores correlated positively with the relationship, suggesting that VGLUT1 may be involved in the physiological processes of learning and memory. Puzzle herbal compound and huperzine pair, SAMP8 hippocampus and cortex VGLUT1 expression results of clinical studies have showed that Angelica and Peony Powder-aligning the side, Huanglianjiedu soup herbal compound has a good therapeutic effect on patients with AD; The large number of experimental pharmacology study results show that Liu Wei Di Huang Tang, Ba Wei Di Huang Tang, due to a variety of reasons animal learning and memory dysfunction role has significantly improved the efficacy of these herbal compound is different. Huperzine A for the drugs commonly used in clinical treatment of AD. Observation the VGLUT1 of these drugs reactivity, the study selected 12-month-old SAMP8, respectively, were given to Liu Wei Di Huang Tang (10g/kg), Ba Wei Di Huang Tang (10.5 g / kg), Angelica and Peony Powder (3.4 g / kg) Spherical square (34.7 g / kg), Huanglianjiedu soup (5 g / kg) and huperzine A (5 × 10 ^{-6 g / kg), for five consecutive weeks. Using real-time quantitative PCR and Western-blot techniques, observation SAMP8 hippocampus and cortex of APP and VGLUT1 gene and protein expression changes. The results show that, compared with their peers SAMR1 of SAMP8 water supply model group, hippocampal the VGLUT1 gene and protein expression were significantly higher, cortical VGLUT1 expression level SAMR1 control group no significant difference in the hippocampus and cortex of APP expression; SAMP8 compared with SAMR1 control group significantly liter high. Giving traditional Chinese medicine and huperzine A treatment, the hippocampus and cortex of SAMP8 and VGLUT1 gene and protein expression were reduced, which addition to the Huanglianjiedu soup group, other administration groups compared with SAMP8 control group with a significant difference. Similar results VGLUT1 drug treatment group SAMP8 hippocampus and cortex of the APP gene and protein expression decreased after administration, except Angelica and Peony scattered in the hippocampus, compared to the other treatment group and control group were statistically significant difference. These results suggest that learning and memory function of the recession and get to learning and memory in the hippocampus and cortex VGLUT1 expression with the central and regular changes occurred, suggesting that the hippocampus and cortical VGLUT1 a close relationship with the central learning and memory function in the central nervous system normal learning and memory function to maintain or adjust the process. In the process of the writing of this article, we found that in April this year Neurobiolgy of Aging on the on-line published the a finalization article, the paper reported that the frontal cortex of AD patients VGLUT1 expression was significantly reduced, and low cognitive function of AD patients were positively correlated. The findings support the conclusions made by this Institute. In addition, the study found that of SAMP8 and give Puzzle drugs, the hippocampus and cortical VGLUT1 expression was significantly reduced, suggesting good reactivity the Puzzle medication has, by regulating the expression of VGLUT1 may be above the Puzzle drugs play puzzle role one of the ways. Therefore, there is reason to believe that, VGLUT1 has become the prevention of the potential value of AD drug screening targets worthy of further study. A large number of findings of SAMP8 and 2-month-old has started learning and memory function damage, followed by a progressive increase 6 months 12 months is more serious. The results of this study show that the SAMP8 hippocampus and cortical VGLUT1 expression curve in the aging process was \high, 12 months to reach 2 months of age, no significant differences compared with their peers SAMR1. In response to this phenomenon, we have made a preliminary analysis. My room past studies have shown that SAMP8 at 2 months of age in the hippocampus and cortical glutamate levels were significantly higher than those of SAMR1 downward trend with increasing age, but still higher than those of SAMR1. The main function is known VGLUT1 glutamatergic neuronal processes in vesicle glutamate transport into synaptic vesicles, is an important factor in regulating glutamate release. Glutamate is involved in the central learning and memory in important physiological processes one of the neurotransmitters, but high concentrations of glutamate has a toxic effect on neurons. Therefore, the normal function of the regulatory system, glutamate neurotransmitter release is normal learning and memory function to maintain the central nervous system and prevent glutamate caused by excessive neuronal damage important conditions. Based on the above findings and analysis, we believe that SAMP8 at 2 months of age when the hippocampus and cortical glutamate levels significantly higher than those of SAMR1 2 to 6 months of age in the hippocampus and cortex VGLUT1 expression amount down a compensatory response, the physiological significance by lowered expression of VGLUT1 and reduce excess glutamate in hippocampus and cortex, in order to maintain normal learning and memory function, and prevent damage to neurons. However, with increasing age and brain aging has been increasing, VGLUT1 regulation dysfunction, decompensation occurs by reducing VGLUT1 expression adjustment mechanism to reduce excessive glutamate in hippocampus and cortex, showed VGLUT1 expression when the pick-up at 12 months of age. In addition, the 12-month-old SAMP8 given puzzle drugs VGLUT1 downregulation its mechanism may be VGLUT1 regulation function improved after administration, by VGLUT1 compensatory mechanisms have been restored to some extent sake. However, our study hippocampal and cortical VGLUT1 and central memory function relationship in its initial stages, pending further study.}

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