1. Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration
- Author
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Bradley D. Gelfand, Yosuke Nagasaka, Peirong Huang, Kenneth M. Marion, Shaobin Wang, Jayakrishna Ambati, Vidya L. Ambati, Shinichi Fukuda, Kirstie Baker, Srinivas R. Sadda, Siddharth Narendran, Akhil Varshney, Ivana Apicella, Meenakshi Ambati, Jan M. Deussing, Praveen Yerramothu, Felipe Pereira, Younghee Kim, Kameshwari Ambati, and Shuichiro Hirahara
- Subjects
Male ,0301 basic medicine ,Cancer Research ,QH301-705.5 ,Retinal Pigment Epithelium ,Drusen ,Article ,Nucleoside Reverse Transcriptase Inhibitor ,Macular Degeneration ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Humans ,Biology (General) ,Receptor ,Innate immunity ,Mice, Knockout ,Amyloid beta-Peptides ,Chemistry ,Purinergic receptor ,Inflammasome ,P2RX7 ,Translational research ,Macular degeneration ,medicine.disease ,eye diseases ,Reverse transcriptase ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,Medicine ,Reverse Transcriptase Inhibitors ,sense organs ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Nonfibrillar amyloid-β oligomers (AβOs) are a major component of drusen, the sub-retinal pigmented epithelium (RPE) extracellular deposits characteristic of age-related macular degeneration (AMD), a common cause of global blindness. We report that AβOs induce RPE degeneration, a clinical hallmark of geographic atrophy (GA), a vision-threatening late stage of AMD that is currently untreatable. We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7, an upstream mediator of NLRP3 inflammasome activation, is required for AβO-induced RPE degeneration. Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors (NRTIs) and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration. These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.
- Published
- 2021
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