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

Alzheimer's disease (AD), characterized by the abnormal accumulation of beta-amyloid (A beta), is the most prevalent type of dementia, and it is associated with progressive cognitive decline and memory loss. A beta accumulation activates microglia, which secrete proinflammatory factors associated with A beta clearance impairment and cause neurotoxicity, generating a vicious cycle among A beta accumulation, activated microglia, and proinflammatory factors. Blocking this cycle can be a therapeutic strategy for AD. Using A beta-activated HMC3 microglial cells, we observed that isorhamnetin, a main constituent of Oenanthe javanica, reduced the A beta-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-kappa B (NF-kappa B). Treatment of the SH-SY5Y-derived neuronal cells with the A beta-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.

Automated summary

Alzheimer's disease is a type of dementia characterized by the abnormal accumulation of beta-amyloid (Aβ). Isorhamnetin, a constituent of Oenanthe javanica, has been shown to reduce inflammation and neurodegenerative presentations in Alzheimer's disease by mediating the IL-6/TYK2 signaling pathway.