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. 2021 Nov 10;7(46):eabi8178. doi: 10.1126/sciadv.abi8178

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Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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Fig. 9. — (A) STAT3 inhibitor C188-9 rescued three AD phenotypes: lipopolysaccharide (LPS)–induced neuroinflammation [interleukin-6 (IL-6) and IL-1β secretion], tau phosphorylation (ptau), and Aβ secretion (Aβ42 and Aβ42:Aβ40). C188-9 reduced IL-6 relative to LPS (blue bar) at the highest concentration (0.6 μM) and reduced release of IL-1β relative to LPS at both 0.3 and 0.6 μM concentrations. For both cytokines, there was a significant increase relative to LPS at the lowest concentration (0.1 μM). C188-9 significantly reduced levels of phosphorylated tau (ptau) relative to VC (blue bar) at the highest concentration (10 μM). C188-9 significantly reduced endogenous Aβ1–42 and Aβ42:Aβ40 ratio relative to VC (blue bar) at the middle concentration (1 μM). (B) The YES1/FYN inhibitor dasatinib reduced levels of total tau and ptau relative to the VC (blue bar) at all three concentrations (0.01, 0.1, and 1 μM). Pro-inflammatory cytokines IL-6 and IL-1β (pg/ml) were measured in the supernatant of BV2 (microglial) cells after 24-hour LPS stimulation and assessed using MSD V-PLEX . Levels of tau (pg tau/μg of total protein) and ptau [arbitrary units (AU)] were measured in lysates from SH-SY5Y cell line overexpressing mutant human tau441 (SH-SY5Y-TMHT441) after 24 hours of stimulation. Levels of Aβ42 and Aβ40 (pg/ml) were measured in the supernatant of murine BV2 (microglial) cells after 3 hours of Aβ stimulation in human APP-overexpressing H4 neuroglioma cells. Blue bars indicate the comparison group: either LPS (stimulation to generate proinflammatory cytokines) for LPS-induced neuroinflammation or the VC for tau phosphorylation and Aβ secretion. Orange bars indicate three increasing concentrations for treatment with C188-9 or dasatinib. Values were compared by one-way ANOVA followed by Dunnett’s multiple comparison test, and significant differences were indicated (*P < 0.05, **P < 0.01, and ***P < 0.001). LPS, lipopolysaccharide; VC, vehicular control (0.1% DMSO); ptau, phosphorylated tau231.