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

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.