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

Abstract

Regulating amyloid beta (A beta) 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 A beta 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 A beta plaque levels in 5x FAD mice by regulating levels of the A beta degradation enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE). Moreover, A beta 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, A beta plaque load, and neuroinflammatory responses in the brain.