Daphnetin ameliorates Aβ pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease. (June 2022)

• Record Type: Journal Article
• Authors: Gao, Peipei; Wang, Zhen; Lei, Mengyao; Che, Jiaxing; Zhang, Shuangxi; Zhang, Tiantian; Hu, Yachong; Shi, Le; Cui, Li; Liu, Jiankang; Noda, Mami; Peng, Yunhua; Long, Jiangang
• Is Part Of: Pharmacological research. Volume 180(2022)
• Publication Date: 2022-06
• Subjects: AD Alzheimer's disease -- ADI Alzheimer's Disease Association International -- APP Amyloid precursor protein -- PS1 Presenilin 1 -- PS2 Presenilin 2 -- Aβ Amyloid-β -- CNS Central nervous system -- GFAP Glial fibrillary acidic protein -- STAT3 Signal transducer and activator of transcription 3 -- p-STAT3 Phosphorylated signal transducer and activator of transcription 3 -- WT Wild type -- AUC Area under the curve -- BACE Beta-site-APP cleaving enzyme -- PEN2 Presenilin enhancer protein 2 -- IDE Insulin-degrading enzyme -- NEP Neprilysin -- ADAM10 A disintegrin and metalloproteinase domain‐containing protein 10 -- RNA-seq RNA-sequencing -- RT–PCR Reverse transcription polymerase chain reaction -- MTT (3-(4, 5-Dimethylthiazol-2-yl)− 2, 5-diphenyltetrazolium bromide; -- TREM2 Triggering receptor expressed on myeloid cells 2 -- GPNMB Glycoprotein nonmetastatic melanoma protein B -- CCL3 Chemokine (C-C motif) ligand 3 -- ST14 Suppression of tumorigenicity 14 -- TLR2 Toll-like receptor 2 -- CST7 Cystatin F -- IL-1β Interleukin-1β -- IL-6 Interleukin- 6 -- TNF-α Tumor necrosis factor-α -- T-AOC Total antioxidant capacity -- SOD Superoxide dismutase -- LPS Lipopolysaccharide -- ELISA Enzyme-linked immunosorbent assay -- ANOVA Analysis of variance -- Nrf2 Nuclear factor E2-related factor 2 -- HO-1 Heme oxygenase 1 -- NF-κB Nuclear factor kappaB -- p65 NF-kappaB p65 -- p-P65 Phospho-NF- kappa-B p65; (PubChem CID: 5280569); AD -- Daphnetin -- Astrocyte -- Aβ -- GFAP -- p-STAT3; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106227
• Languages: English
• ISSNs: 1043-6618

Abstract

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. Graphical Abstract: ga1