The CDK4/6 inhibitor abemaciclib mesylate regulates AD pathology, neuroinflammation and cognitive function through DYRK1A/STAT3 signaling

초록

Aberrant cell cycle re-entry is markedly increased in the patients with Alzheimer's disease (AD) and cyclin-dependent kinases 4/6 (CDK4/6) allows initiation of cell cycle. Therefore, CDK4/6 are possible therapeutic targets for AD, but the effect of CDK4/6 inhibition on AD pathologies in vivo has not been fully addressed. In this study, we investigated the effects of the CDK4/6 inhibitor abemaciclib mesylate on cognitive function and Aβ/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 Aβ-overexpressing model of AD. Abemaciclib mesylate also inhibited Aβ accumulation by enhancing the activity and protein levels of the Aβ-degrading enzyme neprilysin and the α-secretase ADAM17 and decreasing the protein level of the -secretase PS-1 in 5xFAD mice. Importantly, abemaciclib mesylate suppressed tau phosphorylation in 5xFAD mice and tau-overexpressing PS19 mice by reducing DYRK1A and/or p-GSK3β 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.