Isorhamnetin Attenuated the Release of Interleukin-6 from β-Amyloid-Activated Microglia and Mitigated Interleukin-6-Mediated Neurotoxicity

Abstract

Alzheimer's disease (AD), characterized by the abnormal accumulation of β-amyloid (Aβ), is the most prevalent type of dementia, and it is associated with progressive cognitive decline and memory loss. Aβ accumulation activates microglia, which secrete proinflammatory factors associated with Aβ clearance impairment and cause neurotoxicity, generating a vicious cycle among Aβ accumulation, activated microglia, and proinflammatory factors. Blocking this cycle can be a therapeutic strategy for AD. Using Aβ-activated HMC3 microglial cells, we observed that isorhamnetin, a main constituent of Oenanthe javanica, reduced the Aβ-triggered secretion of interleukin- (IL-) 6 and downregulated the expression levels of the microglial activation markers ionized calcium binding adaptor molecule 1 (IBA1) and CD11b and the inflammatory marker nuclear factor-κB (NF-κB). Treatment of the SH-SY5Y-derived neuronal cells with the Aβ-activated HMC3-conditioned medium (HMC3-conditioned medium) or IL-6 increased reactive oxygen species production, upregulated cleaved caspase 3 expression, and reduced neurite outgrowth, whereas treatment with isorhamnetin counteracted these neurodegenerative presentations. In the SH-SY5Y-derived neuronal cells, IL-6 upregulated the phosphorylation of tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription 1 (STAT1), whereas isorhamnetin normalized this abnormal phosphorylation. Overexpression of TYK2 attenuated the neuroprotective effect of isorhamnetin on IL-6-induced neurotoxicity. Our findings demonstrate that isorhamnetin exerts its neuroprotective effect by mediating the neuroinflammatory IL-6/TYK2 signaling pathway, suggesting its potential for treating AD.