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

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

Journal

Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423

Informations de publication

Date de publication:
14 04 2021
Historique:
received: 18 10 2020
accepted: 09 02 2021
revised: 08 02 2021
entrez: 14 4 2021
pubmed: 15 4 2021
medline: 24 3 2022
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41392-021-00537-z PMID: 33850097 PMC: PMC8044134
pubmed: 33850097
doi: 10.1038/s41392-021-00537-z
pii: 10.1038/s41392-021-00537-z
pmc: PMC8044134
doi:

Substances chimiques

Amyloid beta-Peptides 0
Reverse Transcriptase Inhibitors 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

149

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : R01EY028027
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : R01EY29799
Organisme : U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)
ID : R01EY031039

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Auteurs

Siddharth Narendran (S)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Aravind Eye Care System, Madurai, India.

Felipe Pereira (F)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
ORCID: 0000-0001-8884-2816

Praveen Yerramothu (P)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Ivana Apicella (I)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Shao-Bin Wang (SB)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Kameshwari Ambati (K)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Shuichiro Hirahara (S)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Younghee Kim (Y)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Meenakshi Ambati (M)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Center for Digital Image Evaluation, Charlottesville, VA, USA.

Vidya L Ambati (VL)

Center for Digital Image Evaluation, Charlottesville, VA, USA.

Peirong Huang (P)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Akhil Varshney (A)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Yosuke Nagasaka (Y)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Shinichi Fukuda (S)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.

Kirstie L Baker (KL)

Doheny Eye Institute, Los Angeles, Los Angeles, CA, USA.

Kenneth M Marion (KM)

Doheny Eye Institute, Los Angeles, Los Angeles, CA, USA.
ORCID: 0000-0003-1275-5729

Jan M Deussing (JM)

Molecular Neurogenetics, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.

Srinivas R Sadda (SR)

Doheny Eye Institute, Los Angeles, Los Angeles, CA, USA.
Department of Ophthalmology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.

Bradley D Gelfand (BD)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA, USA.

Jayakrishna Ambati (J)

Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA. ja9qr@virginia.edu.
Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA. ja9qr@virginia.edu.
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA. ja9qr@virginia.edu.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA. ja9qr@virginia.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Maladies de l'oeil › Rétinopathies › Dégénérescence de la rétine › Dégénérescence maculaire › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Organes des sens › Oeil › Rétine › Épithélium pigmentaire de la rétine › Nucleoside reverse transcriptase inhibitors...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Inhibiteurs de la transcriptase inverse › Nucleoside reverse transcriptase inhibitors...