The Surprising Nonlinear Effects of S100A9 Proteins in the Retina

• DOI: 10.1021/acschemneuro.3c00650
• Publication Date: 2024-02-07T21:46:38Z
• Authors: Efrat Naaman; Amanda Qarawani; Rony Ben-Zvi Elim...; Michal Harel; Shahaf Sigal-Dror; Shadi Safuri; Vytautas Smirnovas; Ieva Baronaite; Nina V. Romanova; Ludmilla A. Moroz...; Shiri Zayit-Soudry
• Keywords: Electroretinography; Viability assay; S100A9

Age-related macular degeneration (AMD) is a complex disease in which inflammation implicated as key factor but the precise molecular mechanisms are poorly understood. AMD lesions contain an excess of pro-inflammatory S100A9 protein, its retinal significance was yet unexplored. shown to be intrinsically amyloidogenic vitro and vivo. Here, we hypothesized that effects related supramolecular conformation. ARPE-19 cultures were treated with native dimeric fibrillar preparations, cell viability determined. Wild-type rats intravitreally solutions right eye vehicle left. Retinal function assessed longitudinally by electroretinography (ERG), comparing amplitudes configurations for each intervention. Native had no impact on cellular or Despite dispersed intracellular uptake, did not decrease viability. In contrast, fibrils impaired vivo following intravitreal injection rats. Intriguingly, low-dose induced contrasting effects, significantly increasing ERG responses, particularly over 14 days postinjection. The further characterized glial microglial activation. We provide first indication S100A9, showing inflicted dysfunction activation vivo, while low dose same assemblies resulted unpredicted enhancement amplitudes. These nonlinear responses highlight consequences self-assembly insight into pathophysiological possibly physiological roles retina.