Study To The Effect Of Angiotensin Ⅱ Type 1 Receptor Blockage On Learning And Memory And Tau Protein Phosphorylation In Alzheimer Disease Animals

Alzheimer disease (AD) is an age-related chronic neurodegenerated disease featured by progressive memory impairments, cognitive disorder and behavioral change as the most commen type of senile dementia. As the prolongation of life expectancy, its incidence and morbidity rate in aging population keeps increasing yearly. Due to lacking of effective and definite medicine in etilogical treatment and prevention, it spells serious economical and social burden and thus becomes hot spot of neuroscience and neuropharmacology.Biochemical, physiological and functional studies suggest existence of an independent and well-developed focal RAS, in which angiotensinⅡ(AngⅡ) as the most important effector of RAS,produce a marked effect majorly by binding to angiotensinⅡtype 1 receptor (AT1R) and angiotensinⅡtype 2 receptor (AT2R). Selective angiotensinⅡreceptor blockage and target gene researches suggest that RAS implements most function majorly by AT1R.Savaskan et al found AngⅡ,angiotensin convert enzyme(ACE) and AT1R elevated in parietal cortex of AD patient by immunohistochemical method, as wellas strengthened activity of perivascular AngⅡand ACE in cortex. These suggested RAS in the brain was activated during onset of AD and the result was also confirmed in several other experimental studies. These have provided the molecule pathological mechanism basis for Ang II participating in AD morbidity. But besides, the AD animal model studies find that sustained RAS-activating cause the rennin-angiotensinogen transgenic mouse cognition function damage, AT1R blockage can be able to improve study ability and memory function of AD model mouse, these results point out that Ang II maybe participates in AD's happening and the process progressing, and will be the potent target spot that drug interferes with AD. At the same time animal experimental researches discovered AT1R blockage could improve the cholinergic neuron dysfunction and learning memory ability; generous clinical trials also found AT1R blockage could delay memory impairment in AD patient and decrease the morbidity rate of AD. It is evident that RAS participate in onset and development of AD, but the precise mechanism remains unknown. So that this study focused on the protection mechamism of AT1R blockage on cholinergic neuron system and tau phosphorization in AD animals. This stude includes the following two parts. PartⅠInfluence of Irbsartan on memory ability and tau protein phosphorylation on the hippocampus of rats injected Aβ1-42 into cerebral ventrilesObject:To explore the effect of Irbesartan on memory ability and tau protein phosphorylation in the hippocampus of Alzheimer disease rats.Methods:AD rat models were established by injection aggregatedβ-amyloid (1-42) into the cerebral ventricle. Irbesartan at dose of 30mg·kg^-1·d^-1 was administered to Irbesartan-intervention group by intragastric administration .AD model group was given equal physiologic saline by intragastric administration. The administration lasted from 1 week before surgery to 2 weeks after surgery, suspended at the day of surgery. Morris water maze trail was performed to test learning and memory ability. Western blotting was carried out to observe the tau protein phosphorylation. Analytic software was used to determine the OD value of protein strap. Parameters ware analyzed for intergroup differences by one-way ANOVA.Results: The escape latency of AD model group was prolonged (P<0.05) compared to normal control group and sham operation group, while the escape latency of intervention group was not different statistically from normal control group and sham operation group . No difference in total tau protein was observed in four groups ;compared with normal control group and sham operation group, the Ser^199/202Tau protein and the Ser³⁹⁶Tau protein in AD model group were significant increased(P<0.05). Compare with model group, the Ser^199/202Tau protein and the Ser³⁹⁶Tau protein in intervention group were obviously decreased(P<0.05);But no statistical difference was observed between intervention group and the other 2 groups. Conclusion:Irbesartan can attenuate the level of tau protein phosphorylation in the hippocampus of Alzheimer disease rats PartⅡEffect of Lostarn on memory ability and cholinergic neuron system enzyme action in Aizheimer disease transgenic miceObject:To investigate the effect of Losartan on memory ability and cholinergic neuron system enzyme in Alzheimer disease transgenic mice.Methods: Fiive–month-old female transgenic mice were randomly divided into positive control group,low-dosage group,middle-dosage group and high-dosage group. Age-matched female negative homozygote mice were taken as negative control group. Losartan at a different dosage of 0.6g·L-1,0.2g·L-1 and 0.06g/L was dissolved into drinking water and administered to different dosage groups for three months;Two control groups received normal drinking water. Morris water maze trail was performed to test learning and memory ability. Spectrophotometer was carried out to observe the activity of acetyltransferase (ChAT) and True choline esterase (TChE). Parameters ware analyzed for intergroup differences by one-way ANOVA. Results: The escape latency of high-dosage group was significantly shortened (P<0.01) compared to the other groups ; While no significant difference was observed among the other groups.The activitity of ChAT in losartan therapy group showed a dosage dependent elevation , and that in high-dosage group was found significantly increased compared to that in control groups(P<0.01) and the low-dosage group(P<0.05), although the activity of the low-dage group and the middle-group were upregulated (P<0.05)compared with the negative control group, there was no statistical difference between the negative group and the positive group. No statistical difference on TChE activity was observed among 5 groups.Conclusion:Losartan may improve the learning and memery ability and cholinergic neurons function in transgenic mice.