Immunoproteasome inhibition protects the retina from Alzheimer's-associated degeneration

Alzheimer's disease (AD) is marked by progressive cognitive decline and retinal abnormalities, including degeneration of the retinal pigment epithelium (RPE). In models of AD, the accumulation of amyloid-β (Aβ) peptides triggers chronic inflammation and activates the immunoproteasome (iP), primarily driven by tumor necrosis factor-alpha (TNFα) from glial cells. Although pharmacological inhibition of iP has demonstrated protective effects against retinal damage, the precise molecular mechanisms involved remain unclear. In this study, we reveal that Aβ stimulation initiates a signaling cascade from glia to RPE, mediated by TNFα, which in turn promotes iP activation and upregulation of the NLRP3 inflammasome in RPE cells. Aβ exposure significantly increased TNFα secretion in Müller glia, whereas RPE cells exhibited only a minimal intrinsic response to TNFα secretion in response to Aβ. Inhibition of iP reduced TNFα release from glial cells. Additionally, neutralizing gliaderived TNFα decreased iP activity and mitigated epithelialmesenchymal transition (EMT) in RPE cells, highlighting TNFα's crucial role in glial-induced retinal inflammation. These findings position glia-derived TNFα as a central factor in Aβ-induced RPE degeneration through the TNFα-iP-NLRP3 pathway, supporting the use of iP inhibition as a potential therapeutic approach to maintain retinal integrity in AD.