PKM2 Activator TEPP-46 Suppresses Inflammation, Apoptosis, and Oxidative Disordering of Amyloid-Beta Treated Human Neuroblastoma

Abstract

Beta-amyloid peptides (Aβ) are common risk factors associated with cognitive impairment, neuroinflammation, and apoptosis in Alzheimer’s disease (AD). The glycolytic enzyme PKM2 is an essential antioxidant intermediate by promoting glutathione (GSH) biosynthesis, shielding neurons against oxidative damage, and conferring neuroprotective effects. However, its role in AD has rarely been reported. This study aimed to explore the mechanism underlying PKM2 activation in an AD cell model via the PKM2 activator TEPP-46. Aβ administration in SH-SY5Y cells reduced cell viability while increasing inflammation, apoptosis, and oxidative disorder. PKM2 activity, rather than its expression, was reduced in the AD cell model. TEPP-46 administration could restore PKM2 activity, reverse the suppressive effect of Aβ on cell viability and proliferation, reduce the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), decrease Aβ-triggered cell apoptosis, and restore cellular oxidative stress. Furthermore, the effect of TEPP-46 on the AD cell model was confirmed by deactivating P62, reversing the Bax/Bcl-2 ratio, and activating the Nrf2/HO-1 pathway by western blotting. Additionally, colivelin, an Nrf2 antagonist, deactivates the Nrf2/HO-1 pathway and recovers oxidative stress. Colivelin administration could also offset the influence of TEPP-46 on Aβ-induced SH-SY5Y cell inflammation and apoptosis and viability.