2. Academic Validation
  3. 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.
PMID: 35452800 DOI: 10.1016/j.phrs.2022.106227
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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