Cited 4 time in webofscience Cited 7 time in scopus

The novel DYRK1A inhibitor KVN93 regulates cognitive function, amyloid-beta pathology, and neuroinflammation

Title
The novel DYRK1A inhibitor KVN93 regulates cognitive function, amyloid-beta pathology, and neuroinflammation
Authors
Lee, Hyun-juWoo, HanwoongLee, Ha-EunJeon, HyongjunRyu, Ka-YoungNam, Jin hanJeon, Seong GakPark, HyunHeeLee, Ji-SooHan, Kyung-MinLee, Sang MinKim, JeongyeonKang, Ri JinLee, Young-HoKim, Jae-IckHoe, Hyang-Sook
DGIST Authors
Lee, Hyun-ju; Woo, Hanwoong; Lee, Ha-Eun; Jeon, Hyongjun; Ryu, Ka-Young; Nam, Jin han; Jeon, Seong Gak; Park, HyunHee; Lee, Ji-Soo; Han, Kyung-Min; Lee, Sang Min; Kim, Jeongyeon; Kang, Ri Jin; Lee, Young-Ho; Kim, Jae-Ick; Hoe, Hyang-Sook
Issue Date
2020-11
Citation
Free Radical Biology and Medicine, 160, 575-595
Type
Article
Article Type
Article
Author Keywords
DYRK1ALong-term memoryAmyloid betaIDENEPNeuroinflammationMicroglia
Keywords
LONG-TERM POTENTIATIONALZHEIMERS-DISEASEDOWN-SYNDROMEPRECURSOR PROTEINOXIDATIVE STRESSINFLAMMATIONBRAINMICROGLIATAULIPOPOLYSACCHARIDE
ISSN
0891-5849
Abstract
Regulating amyloid beta (Aβ) pathology and neuroinflammatory responses holds promise for the treatment of Alzheimer's disease (AD) and other neurodegenerative and/or neuroinflammation-related diseases. In this study, the effects of KVN93, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), on cognitive function and Aβ plaque levels and the underlying mechanism of action were evaluated in 5x FAD mice (a mouse model of AD). KVN93 treatment significantly improved long-term memory by enhancing dendritic synaptic function. In addition, KVN93 significantly reduced Aβ plaque levels in 5x FAD mice by regulating levels of the Aβ degradation enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE). Moreover, Aβ-induced microglial and astrocyte activation were significantly suppressed in the KVN-treated 5xFAD mice. KVN93 altered neuroinflammation induced by LPS in microglial cells but not primary astrocytes by regulating TLR4/AKT/STAT3 signaling, and in wild-type mice injected with LPS, KVN93 treatment reduced microglial and astrocyte activation. Overall, these results suggest that the novel DYRK1A inhibitor KVN93 is a potential therapeutic drug for regulating cognitive/synaptic function, Aβ plaque load, and neuroinflammatory responses in the brain. © 2020 Elsevier Inc.
URI
http://hdl.handle.net/20.500.11750/12793
DOI
10.1016/j.freeradbiomed.2020.08.030
Publisher
Elsevier Inc.
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