DA-JC1 improves learning and memory by antagonizing Aβ31-35-induced circadian rhythm disorder

Studies have shown that a normal circadian rhythm is crucial to learning and memory. Circadian rhythm disturbances that occur at early stages of Alzheimer's disease (AD) aggravate the progression of the disease and further reduce learning and memory in AD patients. The novel, dual GLP-1R/GIPR agonist DA-JC1 has been found to exert a stronger hypoglycemic effect than a GLP-1R agonist alone and has been shown to exert neuroprotective effects. However, it is not clear whether DA-JC1 improves the Aβ31-35-induced decline in learning and memory ability by restoring disrupted circadian rhythms. In the present study, we carried out a mouse wheel-running experiment and Morris water maze test (MWM) and found that DA-JC1 could effectively improve the decline of learning and memory and circadian rhythm disorders induced by Aβ31-35. After downregulating Per2 expression via lentivirus-shPer2 in the hippocampus and the hippocampal HT22 cells, we found that circadian rhythm disorders occurred, and that DA-JC1 could not improve the impaired learning and memory. These results suggest that DA-JC1 improves damage to learning and memory by antagonizing circadian rhythm disorders induced by Aβ31-35. The outcome of this ongoing study may provide a novel therapeutic intervention for AD in the future.