Aluminum Induced Hippocampus Dendritic Spine Loss By Rac 1/PAK/LIMK/Cofilin Pathway In Rats

Aluminum(Al)has neurotoxicity,can make learning and memory dysfunction.Dendritic spine loss is the pathological characteristics of learning and memory dysfunction.The preliminary study of our group showed that aluminum leads to dendritic spines loss,but the mechanism is not clear.The formation of dendritic spine is mainly dependent on the aggregation and/or depolymerization of actin.The Rac 1/PAK/LIMK/Cofilin signaling pathway plays a key role in this process.However,wether it is involved in Al induced dendritic spine loss is unclear.To investigate the molecular mechanism of dendritic spine loss induced by Al.One hundred and twenty 4-week-old healthy male Wistar rats were randomly divided into 0 mg/kg(control group,CG),50 mg/kg(low-dose group,LG),150 mg/kg(middle-dose group,MG),150 mg/kg(high-dose group,HG)Aluminum trichloride(AlCl3),respectively.Al Cl3 was orally administrated for 90 d.The learning and memory function of rat were measured by Morris water maze(MWM);The body weight and brain weight were measured by electronic balance;Al content in hippocampus was measured by graphite furnace atomic absorption spectrophotometry;The dendritic spine density of hippocampus was detected by Golgi-Cox staining;The protein levels of Rac 1,p-PAK,p-LIMK,p-Cofilin,total Cofilin,F-actin,G-actin and Drebrin A were detected by western blot,the m RNA expressions of Rac 1,Drebrin A and Cofilin were detected by real-time fluorescence quantitative PCR(q RT-PCR);The results showed as follows:(1)In acquisition trial,the latency were significantly higher in MG and HG than CG(P<0.01);The mean time spent in target quadrant were significantly lower in MG and HG than CG(P<0.05;P<0.01);it indicated that Al inhibited the learning function.In probe trial,the number of crossed original platform location were significantly lower in MG and HG than CG(P<0.05;P<0.01),which indicated that Al inhibited momery function.(2)There were no significant difference on the body weight and brain coefficient;The content of Al in hippocampus(LG(4.67±0.15),MG(7.50±0.31)and HG(8.95±0.28))was significantly higher in Al treatment group than those in CG(3.80±0.15)(P<0.05;P<0.01).It indicated that Al accumulated in hippocampus of rats.(3)In the CA1 region,the dendritic spine density of MG and HG were significantly lower than CG(P<0.05;P<0.01);In the DG egion,the dendritic spine density of HG was significantly lower than CG(P<0.01),which indicated that Al suppressed dendritic spine density in the hippocampus.(4)In the MG and HG,the F-actin/G-actin protein rate,the m RNA and protein expressions of Drebrin A were significantly lower than those in CG(P<0.05;P<0.01),it indicated that Al exposure surpressed skeleton protein F-actin formation of dendritic spine.(5)The protein expression of Rac 1、p-PAK、p-LIMK and p-Cofilin were significantly lower in MG and HG than those in CG(P<0.05;P<0.01);The m RNA expression of Rac 1 were significantly lower in MG and HG than those in CG(P<0.05;P<0.01),It indicated that Al inactivated Rac 1/PAK/LIMK/Cofilin pathway,reducing the Cofilin phosphorylation,inhibiting the F-actin formation.Our results suggest Al Cl3 can inhbit Rac 1/PAK/LIMK/Cofilin pathway,reduce F-actin formation,induce dendritic spine loss of hippocampus,and thereby lead to learning and memory deficits.