| First Author | Lee HJ | Year | 2023 |
| Journal | Pharmacol Res | Volume | 190 |
| Pages | 106725 | PubMed ID | 36907286 |
| Mgi Jnum | J:351751 | Mgi Id | MGI:7663190 |
| Doi | 10.1016/j.phrs.2023.106725 | Citation | Lee HJ, et al. (2023) Inhibition of CDK4/6 regulates AD pathology, neuroinflammation and cognitive function through DYRK1A/STAT3 signaling. Pharmacol Res 190:106725 |
| abstractText | Repurposing approved drugs is an emerging therapeutic development strategy for Alzheimer's disease (AD). The CDK4/6 inhibitor abemaciclib mesylate is an FDA-approved drug for breast cancer treatment. However, whether abemaciclib mesylate affects Abeta/tau pathology, neuroinflammation, and Abeta/LPS-mediated cognitive impairment is unknown. In this study, we investigated the effects of abemaciclib mesylate on cognitive function and Abeta/tau pathology and found that abemaciclib mesylate improved spatial and recognition memory by regulating the dendritic spine number and neuroinflammatory responses in 5xFAD mice, an Abeta-overexpressing model of AD. Abemaciclib mesylate also inhibited Abeta accumulation by enhancing the activity and protein levels of the Abeta-degrading enzyme neprilysin and the alpha-secretase ADAM17 and decreasing the protein level of the gamma-secretase PS-1 in young and aged 5xFAD mice. Importantly, abemaciclib mesylate suppressed tau phosphorylation in 5xFAD mice and tau-overexpressing PS19 mice by reducing DYRK1A and/or p-GSK3beta levels. In wild-type (WT) mice injected with lipopolysaccharide (LPS), abemaciclib mesylate rescued spatial and recognition memory and restored dendritic spine number. In addition, abemaciclib mesylate downregulated LPS-induced microglial/astrocytic activation and proinflammatory cytokine levels in WT mice. In BV2 microglial cells and primary astrocytes, abemaciclib mesylate suppressed LPS-mediated proinflammatory cytokine levels by downregulating AKT/STAT3 signaling. Taken together, our results support repurposing the anticancer drug, CDK4/6 inhibitor abemaciclib mesylate as a multitarget therapeutic for AD pathologies. |
