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Oligomeric Aβ1-42 induces an AMD-like phenotype and accumulates in lysosomes to impair RPE function

Oligomeric Aβ1-42 induces an AMD-like phenotype and accumulates in lysosomes to impair RPE function
Oligomeric Aβ1-42 induces an AMD-like phenotype and accumulates in lysosomes to impair RPE function
Alzheimer’s disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ1-42, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lyso-somes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.
Age-related macular degeneration (AMD), Aging, Amyloid beta (Aβ), Autophagy–lysosomal pathway, Retinal pigment epithelium (RPE), Sight loss
2073-4409
1-30
Lynn, Savannah A.
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Johnston, David A.
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Scott, Jenny A.
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Munday, Rosie
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Desai, Roshni S.
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Keeling, Eloise
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Weaterton, Ruaridh
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Simpson, Alexander
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Davis, Dillon
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Freeman, Thomas
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Chatelet, David S.
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Page, Anton
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Cree, Angela J.
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Lee, Helena
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Newman, Tracey A.
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Lotery, Andrew J.
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Ratnayaka, J. Arjuna
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Lynn, Savannah A.
177ed471-999b-4420-b6f6-d24a85b72524
Johnston, David A.
b41163c9-b9d2-425c-af99-2a357204014e
Scott, Jenny A.
a87a2601-b068-4a9a-993a-6bf7e3884d5a
Munday, Rosie
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Desai, Roshni S.
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Keeling, Eloise
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Weaterton, Ruaridh
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Simpson, Alexander
04bf12e8-6eb1-4135-9db0-d521d4a58dd7
Davis, Dillon
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Freeman, Thomas
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Chatelet, David S.
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Page, Anton
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Cree, Angela J.
6724b71b-8828-4abb-971f-0856c2af555e
Lee, Helena
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Newman, Tracey A.
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Lotery, Andrew J.
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Ratnayaka, J. Arjuna
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Lynn, Savannah A., Johnston, David A., Scott, Jenny A., Munday, Rosie, Desai, Roshni S., Keeling, Eloise, Weaterton, Ruaridh, Simpson, Alexander, Davis, Dillon, Freeman, Thomas, Chatelet, David S., Page, Anton, Cree, Angela J., Lee, Helena, Newman, Tracey A., Lotery, Andrew J. and Ratnayaka, J. Arjuna (2021) Oligomeric Aβ1-42 induces an AMD-like phenotype and accumulates in lysosomes to impair RPE function. Cells, 10 (2), 1-30, [413]. (doi:10.3390/cells10020413).

Record type: Article

Abstract

Alzheimer’s disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ1-42, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lyso-somes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.

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Accepted/In Press date: 11 February 2021
e-pub ahead of print date: 17 February 2021
Published date: 17 February 2021
Additional Information: Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
Keywords: Age-related macular degeneration (AMD), Aging, Amyloid beta (Aβ), Autophagy–lysosomal pathway, Retinal pigment epithelium (RPE), Sight loss

Identifiers

Local EPrints ID: 447868
URI: http://eprints.soton.ac.uk/id/eprint/447868
ISSN: 2073-4409
PURE UUID: dd48d7da-8ade-453c-9afb-772f91327360
ORCID for Savannah A. Lynn: ORCID iD orcid.org/0000-0003-2513-3144
ORCID for David A. Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Eloise Keeling: ORCID iD orcid.org/0000-0003-0399-359X
ORCID for Angela J. Cree: ORCID iD orcid.org/0000-0002-1987-8900
ORCID for Helena Lee: ORCID iD orcid.org/0000-0002-2573-9536
ORCID for Tracey A. Newman: ORCID iD orcid.org/0000-0002-3727-9258
ORCID for Andrew J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

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Date deposited: 25 Mar 2021 17:30
Last modified: 06 Jun 2024 02:05

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Contributors

Author: Savannah A. Lynn ORCID iD
Author: David A. Johnston ORCID iD
Author: Jenny A. Scott
Author: Rosie Munday
Author: Roshni S. Desai
Author: Eloise Keeling ORCID iD
Author: Ruaridh Weaterton
Author: Alexander Simpson
Author: Dillon Davis
Author: Thomas Freeman
Author: David S. Chatelet
Author: Anton Page
Author: Angela J. Cree ORCID iD
Author: Helena Lee ORCID iD

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