PFKFB3 Knockdown Attenuates Amyloid β-Induced Microglial Activation and Retinal Pigment Epithelium Senescence

Abstract

Abstract Background: Retinal pigment epithelium (RPE) degeneration is a major cause of irreversible blindness in individuals with age-related macular degeneration (AMD). As the main component of drusen deposits between the retina and RPE cells, amyloid β (Aβ) plays a critical role in activating microglia and causing neuroinflammation in AMD pathogenesis. However, the role of activated microglia-mediated neuroinflammation in progressive RPE degeneration remains unclear. Results: In this study, we mimicked the retinal inflammatory microenvironment of AMD by intravitreal injection of oligomeric Aβ1-40, which resulted in activation of microglia and AMD-like pathology in mice. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a crucial enzyme in microglial metabolic reprogramming and proinflammatory activation, was upregulated in Aβ1-40-treated retina. Proinflammatory activation of microglia driven by upregulating PFKFB3 contributed to RPE degeneration, which was verified in PFKFB3+/− mice, Aβ1-40-activated microglial cell line BV2 and co-culture of RPE cell line ARPE19. RNA sequencing revealed that PFKFB3 knockdown alleviated Aβ1-40-induced microglial neuroinflammatory phenotype in mice. PFKFB3 silencing in microglia inhibited RPE senescence and dysfunction, and rescued the retinal morphology and function. Conclusions: Overall, our findings demonstrated that after Aβ1-40 stimulation, activated microglia-derived neuroinflammatory cytokines may contribute to RPE disorders via PFKFB3. Modulation of PFKFB3-mediated microglial activation might be a promising strategy for AMD treatment.