1. Academic Validation
  2. Daphnetin ameliorates Aβ pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease

Daphnetin ameliorates Aβ pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease

  • Pharmacol Res. 2022 Jun;180:106227. doi: 10.1016/j.phrs.2022.106227.
Peipei Gao 1 Zhen Wang 2 Mengyao Lei 3 Jiaxing Che 4 Shuangxi Zhang 5 Tiantian Zhang 6 Yachong Hu 7 Le Shi 8 Li Cui 9 Jiankang Liu 10 Mami Noda 11 Yunhua Peng 12 Jiangang Long 13
Affiliations

Affiliations

  • 1 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: 519973170@qq.com.
  • 2 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: 1097216506@qq.com.
  • 3 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: 1440166602@qq.com.
  • 4 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: 385815269@qq.com.
  • 5 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: zhangshuang1994@163.com.
  • 6 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: sanjie1993@126.com.
  • 7 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: huyachong@126.com.
  • 8 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: shile@outlook.com.
  • 9 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: cuilitjpu@163.com.
  • 10 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: j.liu@mail.xjtu.edu.cn.
  • 11 Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: noda@phar.kyushu-u.ac.jp.
  • 12 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: y.peng@xjtu.edu.cn.
  • 13 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: jglong@mail.xjtu.edu.cn.
Abstract

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of Amyloid-β peptide 1-40 (Aβ40) and 1-42 (Aβ42) in the cerebral cortex, downregulated the expressions of Enzymes involved in APP processing, e.g., beta-site APP-cleaving Enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aβ deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.

Keywords

(PubChem CID: 5280569); AD; Astrocyte; Aβ; Daphnetin; GFAP; p-STAT3.

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