Hederagenin Modulates M1 Microglial Inflammatory Responses and Neurite Outgrowth

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neurite atrophy and synaptic loss initiate the onset of neuronal death, while the activated M1 microglia-induced neuroinflammatory microenvironment inhibits neurite regeneration and exacerbates neuronal loss. Thus, optimizing the brain microenvironment using small compounds through suppressing activated M1 microglia and promoting neurite regrowth might be an effective therapeutic strategy for AD. We found that hederagenin (HED), a naturally occurring triterpene compound, inhibited lipopolysaccharide-induced nitric oxide generation and downregulated expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6. Further investigation of primary microglia confirmed that HED inhibited Iba-1 positive M1 microglia. However, no changes were seen in CD206 positive M2 microglia polarization. HED remarkably suppressed phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65 signaling. In addition, HED ameliorated Aβ25-35-induced neuritic atrophy and neuronal death. Therefore, HED might be a therapeutic candidate for AD.