Immunoproteasome inhibition protects retinal pigment epithelium from Aβ-induced degeneration via TNFα-NLRP3 pathway.

The retina, particularly the retinal pigment epithelium (RPE), is significantly affected in Alzheimer's disease (AD), exhibiting degeneration alongside cognitive decline. A key driver of AD pathology is the accumulation of amyloid-β (Aβ) peptides, which trigger chronic inflammation. This inflammation activates the immunoproteasome (iP), largely mediated by tumor necrosis factor-alpha (TNFα) secreted from glial cells. While iP inhibition has shown promise in protecting against retinal damage, the precise molecular mechanisms linking Aβ, inflammation, and RPE degeneration remained unclear, representing a critical gap in understanding and therapeutic targeting.

Researchers investigated the signaling cascade between glial cells and RPE cells in response to Aβ stimulation in an in vitro model. They exposed Müller glia and RPE cells to Aβ and measured TNFα secretion. The study then explored the effects of immunoproteasome inhibition on TNFα release from glial cells. Furthermore, they assessed the impact of neutralizing glia-derived TNFα on iP activity and epithelial-mesenchymal transition (EMT) in RPE cells. The primary endpoints included TNFα secretion, iP activation, NLRP3 inflammasome upregulation, and EMT markers in RPE cells.

Aβ stimulation initiated a critical signaling cascade from glia to RPE cells. Exposure to Aβ significantly increased TNFα secretion in Müller glia, while RPE cells showed only a minimal intrinsic TNFα response to Aβ. Inhibition of the immunoproteasome (iP) effectively reduced TNFα release from glial cells, highlighting its role in inflammatory signaling. Crucially, neutralizing glia-derived TNFα led to a decrease in iP activity and mitigated epithelial-mesenchymal transition (EMT) in RPE cells. This demonstrates the central role of TNFα in glial-induced retinal inflammation and RPE degeneration. The findings strongly position glia-derived TNFα as a key mediator in Aβ-induced RPE degeneration.

The study revealed a specific TNFα-iP-NLRP3 pathway as a central mechanism in Aβ-induced RPE degeneration, with iP inhibition disrupting this inflammatory cascade.