Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in Aβ-injected mice.

Age-related macular degeneration (AMD) is mainly characterized by the progressive accumulation of drusen deposits and loss of photoreceptors and retinal pigment epithelial (RPE) cells. Because amyloid β (Aβ) is the main component of drusen, Aβ-induced activated microglia most likely lead to neuroinflammation and play a critical role in the pathogenesis of AMD. However, the relationship between activated microglia-mediated neuroinflammatory cytokines and photoreceptor death has not been clarified. By subretinal injection of Aβ42 in mice, we mimicked an inflammatory milieu of AMD to better understand how activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in the AMD progression. We demonstrated that subretinal injection of Aβ42 induces microglial activation and increases inflammatory cytokine release, which gives rise to photoreceptor apoptosis in mice. Our results were verified in vitro by co-culture of Aβ42 activated primary microglia and the photoreceptor cell line 661W. We also demonstrated that the p38 mitogen-activated protein kinase (MAPK) signaling pathway was involved in Aβ42-induced microglial activation and inflammatory cytokine release. Overall, our findings indicate that activated microglia-derived neuroinflammatory cytokines could contribute to photoreceptor apoptosis under the stimulation of Aβ42. Moreover, this study may provide a potential therapeutic approach for AMD. KEY MESSAGES: Further explore the association between activated microglia-derived neuroinflammatory cytokine secretion and photoreceptor apoptosis under the stimulation of Aβ42. Subretinal injection of Aβ42 induces the activation of microglia and increases proinflammatory cytokines IL-1β and COX-2 expression in the retina, which could give rise to the deterioration of visual function and aggravate photoreceptor apoptosis in mice. Primary microglial are activated and the levels of proinflammatory cytokines are increased by Aβ42 stimulation, which could increase the apoptosis of photoreceptor cell line 661W in vitro. The p38 MAPK signaling pathway is involved in microglial activation and photoreceptor apoptosis under Aβ42 treatment.