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

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

doi:10.1038/s41392-021-00537-z

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

Signal Transduct Target Ther. 2021 Apr 14;6(1):149. doi: 10.1038/s41392-021-00537-z.

Authors

Siddharth Narendran^{1

2

3}, Felipe Pereira^{1

2

4}, Praveen Yerramothu^{1

2}, Ivana Apicella^{1

2}, Shao-Bin Wang^{1

2}, Kameshwari Ambati^{1

2}, Shuichiro Hirahara^{1

2}, Younghee Kim^{1

2}, Meenakshi Ambati^{1

2

5}, Vidya L Ambati⁵, Peirong Huang^{1

2}, Akhil Varshney^{1

2}, Yosuke Nagasaka^{1

2}, Shinichi Fukuda^{1

2}, Kirstie L Baker⁶, Kenneth M Marion⁶, Jan M Deussing⁷, Srinivas R Sadda^{6

8}, Bradley D Gelfand^{1

2

9}, Jayakrishna Ambati^{10

11

12

13}

Affiliations

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 Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA. [email protected].
¹¹ Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA. [email protected].
¹² Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA. [email protected].
¹³ Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / genetics
Amyloid beta-Peptides / metabolism*
Animals
Disease Models, Animal
Humans
Macular Degeneration / drug therapy*
Macular Degeneration / genetics
Macular Degeneration / metabolism
Male
Mice
Mice, Knockout
Retinal Pigment Epithelium / metabolism*
Reverse Transcriptase Inhibitors / pharmacology*

Substances

Amyloid beta-Peptides
Reverse Transcriptase Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding