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한국뇌연구원

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Pharmacol. Res., 2023 Mar 10;106725 | https://doi.org/10.1016/j.phrs.2023.106725 Inhibition of CDK4/6 regulates AD pathology, neuroinflammation and cognitive function through DYRK1A/STAT3 signaling

Hyun-ju Lee ^a, Hyang-Sook Hoe ^a,b

^aDepartment of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Daegu, the Republic of Korea
^bDepartment of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu 42988, the Republic of Korea

Corresponding author : Hyang-Sook Hoe

Abstract

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 Aβ/tau pathology, neuroinflammation, and Aβ/LPS-mediated cognitive impairment is unknown. In this study, we investigated the effects of 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 γ-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-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. AVAILABILITY OF DATA AND MATERIALS: All data generated and/or analyzed during this study are included in this article.

논문정보

형식Research article
게재일2023년 03월 (BRIC 등록일 2023-03-21)
연구진국내 연구진
분야 생명과학 > 신경생물학

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