Gedunin Inhibits Oligomeric Aβ_1-42-Induced Microglia Activation Via Modulation of Nrf2-NF-κB Signaling

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia in aged populations worldwide. The deposition of toxic protein aggregates such as amyloid beta (Aβ) is a hallmark of AD, and there is growing awareness that a key driver of AD pathogenesis is the neuroinflammatory cascade triggered and sustained by these proteins. Consequently, interventions that suppress prolonged neuroinflammation represent viable therapeutic approaches for AD. In this context, we tested the natural product gedunin which is an anti-inflammatory molecule, found in the seeds of the neem tree (Azadirachta indica), whose mechanism of action remains to be fully elucidated. Using a mouse microglia cell line (IMG), we show that gedunin suppresses neuroinflammation arising from Aβ_1-42 oligomer exposure. Our results demonstrate that gedunin suppresses Aβ_1-42-induced NF-κB activation and its targets, including nitric oxide (NO) and IL-1β, known proinflammatory molecules. Further, we show that gedunin inhibits neuroinflammation by activating nuclear factor 2 erythroid-related factor 2 (Nrf2) and its downstream targets γ-glutamylcysteine synthetase, heme oxygenase 1, and NADPH quinone dehydrogenase 1, which are involved in quenching reactive oxygen and nitrogen species (NO) generated by NF-κB activation. Nrf2 activation appears essential for the anti-inflammatory effect because when silenced, the proinflammatory effects of Aβ_1-42 are enhanced and the protective effect of gedunin against NO production is reduced. Additionally, using human neuronal cells (SH-SY5Y), we show that gedunin prevents neurotoxicity secondary to Aβ-induced microglial activation. In conclusion, our findings highlight a potential therapeutic role of gedunin in neurodegenerative diseases.