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AD (Alzheimer’disease) is one of the most common neurodegenerative diseases and the most common type in dementia, as characterized by senile plaques (SP) in the brain cortex, neurofibrillary tangles (NFT), a mass of neuron nuapoptosis and chronic and long term of inflammatory reaction which affected approximately35,600,000patients in the world in2010. The worse thing is the number of AD patients would turn out to be154,000,000in2050. The decreased of cognition and memory with psychiatric diseases are the common symptoms of AD, which badly disturbs normal life for patients and their families. Presenilin is a transmembrance protein including presenilin-1and presenilin-2subtypes, whose gene mutation causes Familial Alzheimer’s disease (FAD). The PS1/PS2double knockout (DKO) mice, which are derived from PS1forebrain-specific knockout mice and PS2knockout mice, exhibit a series of AD-like symptoms, including the impairment of cognition and the degeneration of forebrain. But the mechanism has not been revealed yet.The studies of Epidemiological in human and animals models have shown that neurodegenerative has exists over-activated microglia and astrocyte, which cause the inflammation. It is well known that non-infectious inflammation plays a key role in the development of AD. However, whether inflammation is apathogenic effect or an accompany phenomena has not ever known. Ibuprofen is a most common non-steroidal anti-inflammatory drug using in rodents can reduce inflammation and improve cognitive defects. To test whether Ibuprofen affects the DKO mice and the effect of inflammatory on the development of AD,3-month and6-month old mice were fed with Ibuprofen for6months. Using behavioral and molecular methods to test the effect of Ibuprofen on the neurodegenerative DKO mice and its potential mechanism underlie Ibuprofen improving symptoms of neurodegenerative DKO mice.Most of AD patients suffered from emotional changes, some of which occurred even before clinical symptom. These psychological symptomsbadly affect AD patient’s symptoms and their families’normal lives. In present study, behavioral methods were used to examine the emotional changes related to AD. Also, we want to know whether the DKO is an appreciate model to diagnose the age-related AD and to reveal thepathogenesis of AD.1. The effect of Ibuprofen on neurodegenerative symptoms in DKO mice3-month and6-month DKO mice were fed with Ibuprofen. Then the locomotion, learning and memory, anxiety, depression and apathy were tested using behavioral methods, such as open field, elevated plus maze, forcing swimming, tail suspension. Our results showed that there is no significant effect of ibuprofen on weight, locomotion and depression of both3-month and6-month DKO mice. For3-month DKO mice, although Ibuprofen did not affect forebrain atrophy, it did result in improving short-term learning and memory and anxiety. For6-month DKO mice, although Ibuprofen did not affect anxiety, it did improve leaning and memory and reverse forebrain atrophy.These results indicated that Ibuprofen could improve the neurodegenerative symptom and learning and memory at certain stage at the middle stage development of AD (6-month). However, Ibuprofen did not significantly prevent DKO mice from causing AD disease. 2. The molecular mechanisms of ibuprofen in DKO miceReal-time PCR and Western blotting were used to test the effect of ibuprofen on the expression of some nutritional factors and receptors in brain cortex and hippocampus in DKO mice. We also examined the level of activation in microglia and astrocyte, the degree of Tau protein phosphorylation and the expression of cleaved caspase3after severing. The results showed that there were no significant changes of the expression of FGF2and FGFR2gene in cortex and hippocampus in DKO mice before and after Ibuprofen feeding. For3-month DKO mice, Ibuprofen resulted in decreasing level of over-activated microglia in hippocampus and astrocyte and the phosphorylation of Tau protein in cortex while no change of degree of Tau protein phosphorylation in hippocampus and expression of caspsse-3after severing. For6-month DKO mice, Ibuprofen resulted in improving the level of over-activated microglia, degree of Tau protein phosphorylation and expression of cleaved caspsse-3after severing, however, there is no significant change of level of over-activated astrocyte after Ibuprofen feeding.The results indicated that Ibuprofen resulted in relieving neurodegenerative symptom might be due to relieve the inflammation reaction, which may be an accompany phenomena rather than a pathogenic effect for causing AD disease. Inflammation reactionmight be a protective effectat early life period. The body modulation would be destroyed if the inflammation reaction were inhibited.3. The study on emotion-related behavior in DKO miceIn this experiment, the young (2-month), middle (6-month) and old aged (11-month) control and DKO mice were examined behavioral performances, such as open field, elevated plus maze, forcing swimming, tail suspension, the sweet starch preference, mouse nest building, mouse Resident/intruder, mouse Rota Rod. The results showed that DKO mice had age-related anxiety, depression, anhedonia, apathy, aggression, abnormal motor behavior, which indicated that conditional PS1/PS2gene locked mice had similar emotion-related changes as AD patients and had good age-depended.
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