Contrasting Effects Of Corticosterone Treatment On Amyloid-β,beta-secretase 1 Expression,and Nuclear Factor Kappa B Nuclear Translocation

Background: AD is a very common neurodegenerative disease characterized by impairment in cognition and memory.The main pathological change of AD is the formation of senile plaques with a large amount of Aβ deposition.Patients are mainly elderly people with memory decline,slow in action,and in severe cases they even completely lose the ability to take care of themselves.The high incidence of the disease will not only cause severe physical and psychological harm to the patient,but also bring a heavy burden on the family and society.Unfortunately,the pathogenesis of AD is unclear and the causes are complicated.At present,the hypothesis on the pathogenesis of AD is also diversified,including Aβ deposition theory,tau protein chemistry theory,and neuron fiber tangles(NTFs).In addition,many studies have shown that steroid hormones play a pivotal role in the nervous immune system.Steroid hormones regulates NFKB,which is an important nuclear transcription factor involved in regulating a variety of cellular signaling pathways,including BACE1 signaling pathway.BACE1 is an important enzyme to produce Aβ,NFKB regulates BACE1 expression.So the aims of our study is to explore whether CORT regulates the expression of BACE1 and Aβ,via regulating the NFKB signaling pathway,in order to provide new targets for the treatment of AD.Materials and Methods: In this study,primary neural cells from SD rat embryos at 18 days of pregnancy were prepared.After 10-12 days of culture,the neurons were treated with corticosterone(low-does 100 nM and high-does 1 μM)to simulated the physiological and pathophysiological conditions in the neurons for 30 minutes(acute),24 hours(subacute),or 3 consecutive days(long-term).Then the nuclear extracts were prepared.Western Blot analysis and fluorescent immunohistochemistry were performed to study: 1.whether CORT can regulate the expression of Aβ.2.whether CORT can affect the expression of BACE1.3.whether CORT can regulate the expression and nuclear distribution of NFKB.4.explain that CORT may affect the production of Aβby regulating the expression of NFKB.Protein analysis was performed using the WSB method,intracellular protein fluorescence quantitative analysis was performed usingfluorescent immunohistochemistry,and data were finally analyzed using statistical methods.Results: 1.Treatment with a high dose of 1 μM CORT for 30 minutes significantly reduced the production of BACE1 and the Aβ1-42 reduced.CORT at low and high doses significantly decreased NFKBp65 nuclear localizationthe,but there was no significant effect on the expression level of total protein NFKBp65.2.Treatment with a high dose of 1 μM CORT for 24 hours significantly increased Aβ1-42 and BACE1 expression levels and significantly increased nuclear localization in NFKBp65 but significantly decreased total protein expression levels.3.After 3 consecutive days of CORT treatment,low dose of 100 nM CORT significantly reduced NFKBp65 total protein expression levels,while high dose of 1μM CORT significantly increased NFKBp65 total protein expression levels.CORT treatment at low and high doses for 3 days significantly increased NFKBp65 nuclear localization and upregulated BACE1 expression levels;However,only 1 μM of CORT increased Aβ1-42 expression.Conclusion: We found that CORT regulates NFKB and BACE1 and Aβ in a dose/ time dependent manner.The stress hormone corticosterone(CORT)plays a promoting or inhibitory role in regulating Aβ expression in rat primary cortical neurons through NFKBp65 / BACE1 signaling depending on the concentration and time point.