Endoplasmic Reticulum Stress Mediated Prenatal Stress Promotes The Formation Of Hippocampal Aβ Induced By Offspring Mice Chronic Stress,Which Were Inhibited By Vitamin D

Objective :(1) To explore whether prenatal stress promotes formation of hippocampal Aβ induced by endolasmic reticulum stress, the activated PERK, cause e IF2α phosphorylation, cause BACE1 m RNA translation increases, eventually lead to BACE1 protein content increased.(2) To explore whether vitamn D inhibite offspring hippocampal endoplasmic reticulum stress by giving vitamin D and detecting the expression levels of GRP78, p-PERK, pand p-e IF2α.Methods: The experiment mice were divided into four groups according to the prenatal stress and offspring mice stress: the prenatal control-offspring control group(Control), the prenatal control- the chronic offspring stress group(COS), the chronic prenatal stress-offspring control group(CPS), or the the chronic prenatal stress plus the chronic offspring stress(CPS + COS). ELISA was used to examine the hippocampus levels of amyloid-β protein(Aβ1-42 and Aβ1-40) in the offspring mice; The histopathologic changes in CA3 field of the hippocampus was observed using HE stain; Morris water maze was used to examine learning and memory impairment in mice; Furthermore, western blotting were used to observe the expression levels of Phosphorylation eukaryotic initiation factor 2α(p-e IF2α), Phosphorylation Protein kinase R [PKR]-like ER kinase(p-PERK), glucose-regulated protein 78(GRP78) and β-site APP-cleaving enzyme 1(BACE1) in hippocampus; Additionally, fluorospectrophotometry was used to detect the β-site APP-cleaving enzyme 1 activity; Immunohistochemistry(IHC) technique was used to detect the expression stastus of GRP78. On the basis of the above experiment, The experiment mice were randomly divided into the CPS+COS and prenatal chronic stress- offspring chronic stress- Lavage vitamin D group(CPS+COS+VD). Y maze test was used to investigate the distinctiveness of working memory and reference memory; Western blotting were used to observe the expression levels of p-e IF2α,p-PERK and GRP78; Immunohistochemistry(IHC) technique was used to detect the expression stastus of GRP78.Results: The results of HE showed that in the CA3 field of hippocampus, the disordered arrangement of neurons, decrease in the number of neuron and nuclear pyknosis in the COS group(P<0.05). The results of Morris water maze showed that the COS group mice had more escape latency and swimming distance(P<0.05) compared with the control group, less number of crossing the platform site and swimming time(P<0.05) compared with the control group; Compared with the COS group, the results showed that CPS+COS group mice had more escape latency and swimming distance(P<0.05), less number of crossing the platform site and swimming time(P<0.05). There was no significant difference in BACE1 activity which was determined by fluorescence among the different groups(P > 0.05). There was significant difference in expression of p-e IF2α, p-PERK, GRP78, BACE1, Aβ1-40 and Aβ1-42 in hippocampus between control and COS group(P<0.05). There was significant difference in expression of p-e IF2α, p-PERK, GRP78, BACE1, Aβ1-40 and Aβ1-42 in hippocampus between COS group and CPS+COS(P<0.05). Additionally, The duration of arm visits and the number of arm visits in new arm of CPS+COS+VD was more than CPS+COS group(P<0.05);There was significant difference in expression of p-e IF2α, p-PERK, GRP78 in hippocampus between COS group and CPS+COS(P<0.05).Conclusion:(1) The mechanism may be that prenatal stress activates the PERK, then causes e IF2 alpha phosphorylation, finally promotes increase expression of BACE1 induced by aggravates hippocampal neurons ERS.(2) Moderate vitamin D supplements inhibite that offspring hippocampal endoplasmic reticulum stress by prenatal stress.