Protective Effect Of Atorvastatin On Amyloid-β Oligomers Induced Neurotoxicity And The Underlying Mechanisms In Rat Hippocampus

ObjectiveEpidemiological evidence suggests that long-term treatment with statinsdecreases the risk of developing Alzheimer’s disease (AD). The present studywas designed to investigate whether in vivo atorvastatin treatment couldprotect rats against amyloid-β peptide oligomer (AβO)-induced synaptotoxicityand memory dysfunction and to determine the putative mechanisms involvedin the neuroprotection induced by atorvastatin.MethodsWe established an AD rat model using an intracerebroventricular injectionof AβOs. A Morris water maze task was performed to determine the spatiallearning and memory ability in this AD model. The concentrations of interleukinIL-1β, IL-6, and tumor necrosis factor-α (TNF-α) were determined in thehippocampus using ELISA assays9days after the injection of AβOs. Culturedhippocampal neurons were incubated with AβOs for48h. Atorvastatin orSB203580was added1h or30min prior to the addition of AβOs.Immunofluorescence was used for the detection of microtubule-associatedprotein-2(MAP-2) and synaptophysin in cultured hippocampal neurons. Theprotein levels of synaptophysin, postsynaptic density-95(PSD-95), andphospho-p38mitogen-activated protein kinase (p38MAPK) in rat hippocampusor cultured hippocampal neurons were evaluated using Western blot analyses.Male Sprague-Dawley rats weighing250–300g were used throughout thestudy. We injected soluble Aβ1-42into lateral ventricles, and ventralhippocampal microdialysis samples were collected at2,24,48,72, and96hours from conscious, freely-moving rats. The samples were automaticallyanalyzed by high-performance liquid chromatography. ResultsThe intracerebroventricular administration of soluble AβOs inducedsevere memory impairments in the Morris water maze task, the loss ofsynaptic proteins synaptophysin and PSD-95, and a strong inflammatoryreaction characterized by increased IL-1β, IL-6, and TNF-α production. Theincreased inflammatory reaction was accompanied by an increased activationof p38MAPK. These effects were prevented by atorvastatin treatment in rats.In addition, atorvastatin treatment prevented AβO-induced synaptotoxicity (i.e.,the loss of MAP-2, synaptophysin, and PSD-95) in a concentration-dependentmanner in cultured hippocampal neurons. Pretreatment of hippocampalneurons with the p38MAPK inhibitor SB203580also prevented the AβO-induced loss of synaptophysin and PSD-95.Our microdialysis results revealed that NA levels were significantlyincreased at24and48hours, but decreased at96hour. We also found thatEpi levels were significantly increased, but5-HT and5-HIAA levels weredecreased from24to96hours. These results suggest that the monoamineneurotransmitters in the hippocampus seem to be more acutely susceptible tothe effect of soluble Aβ1-42. Atorvastatin treatment partly inhibited AβO-inducedthe changes of NA. In addition, atorvastatin treatment also partly inhibitedAβO-induced increase in Epi level and AβO-induced decrease in5-HT and5-HIAA levels in the hippocampaus.of conscious, freely-moving rats.Conclusions1. Atorvastatin can significantly improve AβO-induced induced spatiallearning and memory disorders in rats2. The effect of atorvastatin against AβO-induced induced spatial learningand memory deficits of rats may be associated with upregulating SYP, PSD-95protein expression levels. 3. Atorvastatin can prevente AβO-induced monoamine neurotransmitterchange.4. The neuroprotective effect of atorvastatin may be related to inhibitingp-p38MAPK signal transduction pathways and inflammatory factor release.