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Amyloid‐Beta Mediated Pro‐Oxidative Effects in Human Retinal Cells Involve the Small GTPase Rac‐1: Potential Therapeutic Role of FTI277 for Age‐Related Macular Degeneration
Author(s) -
OwensWalton Jeunice,
Thounaojam Menaka,
Gutsaeva Diana,
Bartoli Manuela
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.463.6
Subject(s) - reactive oxygen species , oxidative stress , microbiology and biotechnology , drusen , retinal , retinal pigment epithelium , chemistry , small gtpase , macular degeneration , biology , biochemistry , signal transduction , medicine , ophthalmology
There is a need for new therapies for age‐related macular degeneration (AMD), the leading cause of blindness in elderly. Fibrils of amyloid beta (Aβ), a causative factor of Alzheimer's disease (AD), have been identified among the constituents of “drusen”, yellowish deposits located in the retinal pigment epithelium (RPE) of AMD patients and considered diagnostic hallmarks of the disease. Increased production of reactive oxygen species in RPE is in important pathogenic step for AMD and involves NAD(P)H oxidases such as NOX2 and NOX4. Here we have conducted a study analyzing the effects of oligomers of Aβ (1–42) in inducing oxidative stress in human retinal pigment epithelial cells (HRPE) and evaluated the role of the small GTPase Rac‐1, required for NOX2 and 4 activation, in this process. Using a Cell‐ROX assay we found that Aβ (1–42) (5mM for 12hours) stimulated the formation of reactive oxygen species (ROS) in HRPE. Aβ (1–42)‐promoted ROS production and contemporaneous activation of Rac‐1, measured by translocation of the protein to the plasma membrane (cell fractionation and Western blotting) and by increased ratio of the GTP bound versus the GDP bound form of the protein (assessed by immunoprecipitation). Same doses of the inverse peptide Aβ (42‐1), used as negative control, had no effects. Activation of Rac‐1 is preceded and dependent on farnesylation. Treatment of the cells with the farnesyl transferase inhibitor FTI‐277 (25mM) blocked Aβ (1–42)‐induced activation of Rac‐1 and consequent ROS formation in HRPE. In summary, our results suggest a role for Aβ in promoting oxidative stress and dysfunction of the RPE, two effects seen during AMD. In addition, we have identified FTI‐277 as a potential new therapy for AMD because on its inhibitory effects towards Rac‐1. Support or Funding Information Supported by the Medical Scholars Program, Medical College of Georgia, Augusta, GA. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .