The Role Of The Interaction Between HIF-1α And Notch-1in Alzheimer’s Disease

Objective:To investigate the relationship between HIF-1a and Notch1in central nervous system and what role they have played in the development of Alzheimer’s disease (AD).Methods:In this study, mouse cortical neurons and glial cells were co-cultured in vitro. And the genes of HIF-1a and Notch1of the co-clutured cells were muted by electroporation transfection. Then the expression levels of Notch1and HIF-1a were detected by RT-PCR and Western Blot. Aβ oligomers (ADDLs) was applied to intervene the co-culture system to mimic an AD model in vitro. After that, Western Blot was applied to detect the expression of HIF-1a and Notch1proteins and RT-PCR was used to detect the expression of caspase-3mRNA in the AD model in vitro under different conditions. APPSWE transgenic mice was applied as the AD model mice. HIF-1a and Notchl were measured in the brains of AD model mice under different conditions.Results:First of all, the inhibition of HIF-1a and Notchl genes reduced the expression of Notchl and HIF-1a in the co-cultured neurons and glial cells respectively. Second of all, ADDLs induced the expression of HIF-1a and Notchl in the AD model in vitro and the expression of HIF-1α was positively correlated with Notch1. While the gene silencing of HIF-1a and Notch1could reverse the effect of ADDLs. ADDLs promoted the expression of caspase-3in the AD model in vitro. And this trend could be retrieved by HIF-1a and Notchl gene silence at4hours after ADDLs intervention. While this kind of protective effect of HIF-1a and Notch1gene silence could be extinguished at24hours after ADDLs intervention. Finally, the expression of HIF-1a and Notch1were up-regulated in the APPSWE mice brains compared with that in the wild type mice brains. Acute anoxia induced the expression of HIF-1a and Notch1in both APPSWE mice brains and wild type mice brains. While this kind of uptrend was more obvious in wild type mice. And the expression of HIF-1a is directly related with Notchl.Conclusion:HIF-1a is closely and positively related with Notchl in normal central nervous system and in AD models both in vitro and in vivo. HIF-1a and Notchl have taken part in the cell apoptosis indued by ADDLs. Therefore, HIF-1a and Notch1may play an important role in the development of AD.