Inhibition of CDK4/6 regulates AD pathology, neuroinflammation and cognitive function through DYRK1A/STAT3 signaling

초록

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 A beta/tau pathology, neuroinflammation, and A beta/LPS-mediated cognitive impairment is unknown. In this study, we investigated the effects of abemaciclib mesylate on cognitive function and A beta/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 A beta-overexpressing model of AD. Abemaciclib mesylate also inhibited A beta accumulation by enhancing the activity and protein levels of the A beta-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-GSK3 beta 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.

키워드