Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-βinduced retinal pigmented epithelium degeneration  

作　　者：Siddharth Narendran Felipe Pereira Praveen Yerramothu Ivana Apicella Shao-bin Wang Kameshwari Ambati Shuichiro Hirahara Younghee Kim Meenakshi Ambati Vidya L.Ambati Peirong Huang Akhil Varshney Yosuke Nagasaka Shinichi Fukuda Kirstie L.Baker Kenneth M.Marion Jan M.Deussing Srinivas R.Sadda Bradley D.Gelfand Jayakrishna Ambati 

机构地区：[1]Center for Advanced Vision Science,University of Virginia School of Medicine,Charlottesville,VA,USA [2]Department of Ophthalmology,University of Virginia School of Medicine,Charlottesville,VA,USA [3]Aravind Eye Care System,Madurai,India [4]Departamento de Oftalmologia e Ciências Visuais,Escola Paulista de Medicina,Universidade Federal de São Paulo,São Paulo,Brazil [5]Center for Digital Image Evaluation,Charlottesville,VA,USA [6]Doheny Eye Institute,Los Angeles,Los Angeles,CA,USA [7]Molecular Neurogenetics,Department of Stress Neurobiology and Neurogenetics,Max Planck Institute of Psychiatry,Munich,Germany [8]Department of Ophthalmology,David Geffen School of Medicine,University of California–Los Angeles,Los Angeles,CA,USA [9]Department of Biomedical Engineering,University of Virginia School of Medicine,Charlottesville,VA,USA [10]Department of Pathology,University of Virginia School of Medicine,Charlottesville,VA,USA [11]Department of Microbiology,Immunology,and Cancer Biology,University of Virginia School of Medicine,Charlottesville,VA,USA

出　　处：《Signal Transduction and Targeted Therapy》2021年第5期1526-1534,共9页信号转导与靶向治疗（英文）

基　　金：J.A.has received support from NIH grants(R01EY028027,R01EY29799,R01EY031039);DuPont Guerry,III,Professorship,a gift from Mr.and Mrs.Eli W.Tullis,and the University of Virginia Strategic Investment Fund;B.D.G.has received support from NIH grants(R01EY028027 and R01EY031039);BrightFocus Foundation,and the Owens Family Foundation.

摘　　要：Nonfibrillar amyloid-βoligomers(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.

关 键 词：DEGENERATION ACTIVATION UPSTREAM 

分 类 号：R774.1[医药卫生—眼科]