KRICT-9 inhibits neuroinflammation, amyloidogenesis and memory loss in Alzheimer’s disease models

Abstract

Alzheimer’s disease (AD) is one of the most common forms of dementia and is characterized by neuroinflammation and amyloidogenesis. Here we investigated the effects of KRICT-9 on neuroinflammation and amyloidogenesis in in vitro and in vivo AD models. We found that KRICT-9 decreased lipopolysaccharide (LPS)-induced inflammation in microglial BV-2 cells and astrocytes while reducing nitric oxide generation and expression of inflammatory marker proteins (iNOS and COX-2) as well as APP, BACE1, C99, Iba-1, and GFAP. KRICT-9 also inhibited β-secretase. Pull-down assays and docking model analyses indicated that KRICT-9 binds to the DNA binding domain of signal transducer and activator of transcription 3 (STAT3). KRICT-9 also decreased β-secretase activity and Aβ levels in tissues from LPS-induced mice brains, and it reversed memory impairment in mice. These experiments demonstrated that KRICT-9 protects against LPS-induced neuroinflammation and amyloidogenesis by inhibiting STAT3 activity. This suggests KRICT-9 or KRICT-9-inspired reagents could be used as therapeutic agents to treat AD.