Dissertation > Medicine, health > Neurology and psychiatry > Psychiatry > Cerebral organic mental disorder > Elderly as early as possible the old disorder

Study to the Effect of Angiotensin Ⅱ Type 1 Receptor Blockage on Learning and Memory and tau Protein Phosphorylation in Alzheimer Disease Animals

Author ZuoQiang
Tutor ShiJingPing
School Nanjing Medical University
Course Neurology
Keywords Alzheimer's disease APPswePS1dE9 transgenic Angiotensin Ⅱ Water maze tau protein
CLC R749.16
Type Master's thesis
Year 2009
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The AT1R antagonist of Alzheimer's disease animal study of learning and memory and tau phosphorylation affect Alzheimer's disease (Alzheimer disease, AD) in progressive memory impairment, cognitive impairment and behavioral changes as the main manifestation of chronic neurodegenerative diseases , senile dementia, the most common type. With the longer life expectancy of the population, its incidence and prevalence in the elderly population has increased every year. Due to lack of credible etiology, treatment and prevention of drug thus bring serious economic and social burden, thus becoming the world neuroscience and neuropharmacology research hotspot. Biochemistry, physiology, and functional studies found that the brain exists independent perfect renin - angiotensin system (rennin-angiotensin system, RAS), angiotensin Ⅱ (Ang Ⅱ) is the most important active ingredients in the RAS, mainly through its type 1 receptor (angiotensin Ⅱ type 1 receptor, AT1R) and type 2 receptor (angiotensin Ⅱ type 2 receptor, AT2R) combined to play a role, the selective AT1R and AT2R antagonist and target genes confirmed the vast majority of RAS function by AT1R mediated guide. Savaskan et al study found that the brains of patients with AD parietal cortex ACE by immunohistochemistry method of AngII and AT1R expression levels increase, in addition to discovery the cortical perivascular's AngII and ACE activity increased, the study showed that the brain of AD patients RAS in the pathogenesis is activated, in some studies also been confirmed. This provides the basis of the molecular pathology involved in the pathogenesis of AD Ang Ⅱ. In addition, AD animal model studies found that renin / angiotensinogen transgenic mice cognitive dysfunction can be caused by continuing RAS activation to AT1R antagonist AD model mice can improve learning and memory function, these results suggest that Ang Ⅱ may be through its type 1 Ang Ⅱ receptor (angiotensin Ⅱ type 1 receptor, AT1R) mediates involved in the onset and progression of AD, is a potential target for AD intervention. And animal studies found that The AT1R antagonist improving cholinergic neuronal dysfunction improve learning and memory ability, a large number of clinical trials research also found that AT1R antagonists delay AD patients with learning and memory impairment to reduce the prevalence of AD; prompted RAS involved in the pathogenesis of AD, However, the specific mechanism remains unclear. Therefore, this study focuses on the cholinergic system and tau protein phosphorylation explore AT1R antagonist mechanisms of the protective effect in AD. The experiments include the following two parts: the first part: the purpose of irbesartan Aβ1-42 intracerebroventricular injection of rat learning and memory and hippocampal tau protein phosphorylation research irbesartan study of Alzheimer disease (AD) rats memory capacity and the impact of of hippocampal tau protein phosphorylation. Aβ1-42 production method intracerebroventricular injection of oligomeric forms of AD model; irbesartan intervention group were given irbesartan 30mg · kg-1 · d-1 ig AD model group were given the same amount of saline irrigation stomach, since the preoperative one week to two weeks after continuous administration, the day of surgery suspend administered once. Morris water maze test for detection of learning and memory ability was detected by Western blot, the hippocampal tau protein serine 199/202 points, 396 points phosphorylation; analysis software measured with western blot image strip optical density (OD) value of single-factor analysis of variance The differences among the groups. Morris water maze test results (1) AD model group escape latency than the normal control group and the sham group leader (P lt; 0.05), irbesartan intervention group and normal control group, sham group and model group difference was not statistically significance. (2) 4 groups hippocampal tau protein total difference was not statistically significant; (3) compared with the normal control group and the sham group, the AD model group serine 199/202 (tau1) sites and 396 points phosphorylated tau The protein content increased significantly (all P lt; 0.05), irbesartan group of serine tau1 and 396 points phosphorylated tau protein levels significantly lower than the AD model group (P lt; 0.05). Conclusion Irbesartan can reduce the AD rat hippocampal tau phosphorylation levels. Part II: Effects of losartan on Aizheimer disease transgenic mice learning and memory and cholinergic system activity affect the purpose of losartan Aizheimer disease transgenic mice learning and memory and the cholinergic system activity. Method 5-month-old female APPswePS1dE9 positive transgenic mice were randomly divided into the positive control group, low-dose group, middle dose group and high dose group, female APPswePS1dE9 negative homozygous for the negative control group, losartan dissolved in drinking water dubbed 0.6g · L-1, 0.2g · L-1, 0.06 g · L-1, the control group given normal drinking water for consecutive 3 months; Morris water maze test for detection of learning and memory abilities, spectrophotometric detection The mouse cortex choline acetyltransferase (choline acetyltransferase, ChAT) and acetylcholinesterase (True choline esterase TChE) active, single-factor analysis of variance to compare differences between groups. Results with the average incubation period of the group compared to the high dose group was significantly shorter (P lt; 0.01), while no significant difference among other groups. Losartan treatment group ChAT activity in a dose-dependent increase in the high dose group ChAT activity was significantly increased (control group than the P lt; 0.01, with the low-dose group than P lt; 0.05); compared with the negative control group, low-dose group ChAT activity and middle dose group were significantly increased (P lt; 0.05); while no significant difference between the two control groups; TChE activity among groups Conclusion Losartan no significant difference in to increase transgenic mice learning and memory capacity and improve choline neurons

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