The Effects Of Oxidative/psychological Stress On Cognition And Aβ Metabolism-associated Molecules

Oxidative and psychological stresses are unavoidable pathological and physiological events correlated withβ-amyloid(Aβ) which is one of pathological characters of AD.It is still unknown whether oxidative or(and) psychological stressors might influence Aβ1-42 expression and its metabolism-associated molecules in brain.To elucidate these questions, bellowed studies were performed:First,to determine a suitable dosage of D-galactose(D-gal) for oxidative stress. According to the statistical data of references,we chose dosages of 75,120,150 and 1000mg/kg for 8-week injection and explore the effects of D-galactose on anti-oxidative enzymes and cognitive functions.The results suggested that D-galactose of four dosages could induce significantly cognitive defects,decrease of superoxide dismutase(SOD) and catalase(CAT) activities,increase of malondialdehyde(MDA) content.However.the effect of D-galactose on indicators was different in each dosage.We finally chose 120mg/kg as the most suitable dosage according to mentioned above detections combining with general conditions of the mice during D-galactose treatment.Second,acute restraint stress was used to establish psychological stress animal models and then to explore the effect of oxidative,psychological and combined stresses on cognition, anti-oxidative enzymes,corticosterone content and Aβ1-42 expression by the methods of behavior tests,biochemistry,radio-immunity assay and immunohistochemistry.The results indicated that the activities of SOD and CAT decreased,but MDA content increased in three stress groups.Moreover,psychological and combined stresses could enhance corticosterone levels.Therefore,the animal models of oxidative or(and) psychological stresses were feasible. D-galactose mainly impaired spatial cognition but acute restraint stress and combined stress could lead to both spatial and non-spatial cognition impairment.All the three stresses could upregulate Aβ1-42 expression and the increase in combined group was higher than any single stress group.Third.the study discussed the molecular mechanism of Aβ1-42 metabolism induced by D-galactose,acute restraint stress and combined stress by the methods of western blotting and RT-PCR.The results suggested that Aβ1-42 metabolism was involved in generation, degradation and transportation in which the increase of Aβ1-42 level mostly caused by upregulation of BACE1 expression.Matrix metalloproteinases-2(MMP-2) and insulin-degrading enzyme(IDE) were participated in degrading Aβ1-42.However,IDE increase in acute restraint stress but not D-galactose indicated that Aβ-degrading enzymes may be selectively role in different stress conditions.LRP-1 mediates a continuous efflux of brain Aβ1-42 into the circulation.This study found that LRP-1 in mice treated with D-galactose,acute restraint stress and in combination was higher than that of control. Furthermore,this study did not find any significant difference of RAGE expression between any treated group and control.The increase of LRP-1 and no change in RAGE may contribute to Aβ1-42 efflux and prevent Aβ1-42 accumulation in the brain.The higher expression of BACE1 in combination group than any of single stress group was perhaps associated with collaboration of D-galactose and acute restraint stress.Moreover,the higher expressions of MMP-2 and LRP-1 in combined stress group than that of in D-galactose or acute restraint stress group were compensatory for Aβ1-42 clearance.