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

// Do Yeon Lee 1 , Chul Ju Hwang 1 , Ji Yeon Choi 1 , Mi Hee Park 1 , Min Ji Song 1 , Ki Wan Oh 1 , Sang Bae Han 1 , Woo Kyu Park 2 , Hee Yeong Cho 2 , Sung Yun Cho 2 , Hye Byn Park 2 , Min Jong Song 3 and Jin Tae Hong 1 1 College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Chungbuk 361-951, Republic of Korea 2 Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon 34114, Republic of Korea 3 Department of Obstetrics and Gynecology, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Jung-gu, Daejeon 301-723, Republic of Korea Correspondence to: Jin Tae Hong, email: jinthong@chungbuk.ac.kr Keywords: Alzheimer’s disease, STAT3, neuroinflammation, amyloidogenesis, KRICT-9 Received: January 09, 2017     Accepted: June 24, 2017     Published: August 02, 2017 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.