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Effect of Alpha-lipoic Acid on PKA-CREB Signal Path in the Hippocampus of Alzheimer’s Disease Model Rats

Author: YangLiPing
Tutor: ZhangGuoHua
School: Hebei Medical University
Course: Neurology
Keywords: Alzheimer’s disease PKA CREB alpha-lipoic acid
CLC: R-332
Type: Master's thesis
Year: 2013
Downloads: 38
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Abstract


Objective：Alzheimer’s disease (AD), a kind of dementia which is closelyrelated to age, is the most common form of neurodegenerative disease anddementia. The classical clinical manifestation is slowly progressive memoryand cognitive dysfunction and the damage of behaviors. The characteristicpathologic alterations are senile plaques (SP) composed largely of amyloidβ-peptides (Aβ) outside cells of the cerebral cortex and hippocampus, andneurofibrillary tangles (NFT) in cells and selective neuron loss. As the agingof the population acceleration in our country, Incidence of AD increasing yearby year, researching new therapeutic targets and treatment is of greatsignificance.Cyclic-AMP(cAMP) dependent protein kinase A(PKA) is a kind of thecAMP actived protein kinase. PKA is a tetrameric holoenzyme consisting oftwo regulatory subunits (R subunits) and two catalytic subunits(C subunits).Several isoforms of both C subunit (Cα, Cβ, and Cγ) and R subunit (RIα, RIβ,RIIα and RIIβ) have been found in mammalian tissue. PKA is activated bycAMP disassociating the R subunits from the C subunits. The activated PKAthen moves into the cell nucleus, where it activates CREB Ser133byphosphorylating it. Phosphorylation of CREB and cAMP response element(CRE) activate directly or indirectly transcription of related genes，and expresscertain protein molecules and some neurotrophic factors such as B cellleukemia／lymphoma-2(bcl-2)，brain derived neurotrophic factor(BDNF) andso on, thus inhibiting apoptosis, promoting cell differentiation and generationof cells to repair after injury and so on.At present, drugs of slowing effectively AD can be counted on one’sfingers, and research and treatment of AD new and more effective drug comehot. Alpha-lipoic acid(α-LA) is a kind of unique oxidation-reduction two-way oxidative stress of powerful inhibitors. It is mainly throughscavenging free radicals， chelating metal ions， recycled from otheranti-oxidants play its antioxidant activity.This study is designed to establish a rat model of AD，and detect theExpression of the PKA and p-CREB levels in the rat hippocampus. Whileobserving the effect of α-LA on the level of PKA and p-CREB expression inthe AD rat hippocampus．Discussing the protective effect of α-LA on theinjury of central nervous system and its mechanism, which provides a morefavorable theoretical basis for clinical administration．Methods：SD rats were randomly divided into4groups：the normalcontrol group，sham-operated group，model group，alpha-lipoic acid group，and each group had6mouse．Bilateral hippocampus were injected condensedAβ1-42to be prepared for rat model of AD．alpha-lipoic acid group which wasgiven intraperitoneally100mg/kg·d alpha-lipoic acid, other groups were givenintraperitoneally equal volume of saline, once a day. We used Morris watermaze to test rats’ incubation period and to observe the influence of rats ofalpha-lipoic acid treatment in incubation period after21days treatment. Theexpression difference of PKA and p-CREB in the hippocampus of rats indifferent groups have been investigated with Western blot technique．Results:1. Compared latent phase and the number across the platform of rats watermaze each group①In positioning navigation experiment, latent phase among normalcontrol group, sham-operated group and LA group decreased obviously，butthat was not obvious in model group. Compared with sham-operated group,the escape latency of rats in model group rats was longer than the former，there was a statistical significance group(P<0.01); Compared with modelgroup, the latent phase of rats in LA group was significantlyshortened(P<0.01), suggesting alpha lipoic acid increased significantly interms of learning and memory in rats of AD group; Compared with the normalgroup，there was no statistical significance in sham-operated group(P>0.05). ②In space exploration experiments，compared with the sham-operated group，the reduction of the number across the platform in model group of rats was astatistical significance (P<0.01)；Compared with model group，the memory ofrats in LA group was improved，there was a statistical significance (P<0.01);There was no statistical significance between sham-operated group and normalgroup (P>0.05).2. Compared expression level of PKA Ⅱα and p-CREB in thehippocampus of rats with Western blot technique．Compared with the sham-operated group, it was significant thatexpression of PKAⅡαand p-CREB in the hippocampus of model groupdecreased obviously(P<0.01). Compared with model group，PKAⅡαandp-CREB expression of LA group in the hippocampus of rats enhancedsignificantly(P<0.01). Expression level of PKAⅡα and p-CREB of normalcontrol group and sham-operated group don’t have no statistical significance(P>0.05).Conclusions：Bilateral hippocampus Aβ1-42one-time injection of thepreparation of rat model successfully simulates the behavior characteristics.PKA-CREB Signaling pathway involve in learning and memory impairmentof AD process in hippocampal neurons. Alpha-lipoic acid can effectivelyalleviate the damage of hippocampal neurons in AD rats so as to faci1itate thesignal transduction pathway related to learning and memory normally，enhance the learning and memory of AD rats．

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