Dulaglutide Alleviates Alzheimer's Disease by Regulating Microglial Polarization and Neurogenic Activity

Backgrounds: Increasing research has proved that microglial activation, polarization, and inflammatory response in the brain affect the pathology of Alzheimer's disease. Hence, employing reagents targeted to microglial functions to optimize the brain microenvironment may become a promising therapeutic method for Alzheimer's disease. Methods: The phagocytosis and clearance of Aβ1-42 were detected using western blot and immunofluorescence assay. The cell viability was determined via 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) or cell counting kit-8 (CCK-8) assay. The load of pro-inflammation in addition to anti-inflammation factors was measured through enzyme-linked immunosorbent (ELISA) assay. Flow cytometry was employed to estimate the apoptotic cells. The protein level related to microglial polarization and neuronal injury was detected via western blot. The length of the neuronal synapse was investigated by using an immunofluorescence assay. Results: Dulaglutide significantly promoted microglia to phagocytose and get rid of the Aβ plague. Additionally, dulaglutide treatment inhibited the production of pro-inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin -1β, and IL-6, whereas increased the load of anti-inflammatory molecules such as IL-10 affected by Aβ1-42 exposure. Further investigation verified that Aβ1-42 down-regulated YM1/2 positive M2 microglial polarization phenotype but up-regulated cyclooxygenase-2 (Cox2) positive M1 microglia. However, treating with dulaglutide effectively counteracted these effects. Moreover, dulaglutide dramatically recovered primary cortical neuron cells viability and inhibited cells apoptosis influenced by Aβ1-42. Furthermore, the dulaglutide also reversed neuronal synapse injury after exposure to Aβ1-42. Conclusion: Altogether, this investigation verified that dulaglutide improved Aβ-induced inflammation and neuronal injury by mediating the activation and polarization of microglia, thereby alleviating Alzheimer's disease efficiently.