The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Dementia of the Eye- Alzheimer’s-linked Amyloid beta proteins provide new insights into retinal degeneration

Dementia of the Eye- Alzheimer’s-linked Amyloid beta proteins provide new insights into retinal degeneration
Dementia of the Eye- Alzheimer’s-linked Amyloid beta proteins provide new insights into retinal degeneration
Purpose: age-related Macular Degeneration (AMD) is the most common cause of irreversible blindness in the developed world for which there is no effective treatment. Advanced stages of the disease manifests as two broadly-defined phenotypes; geographic atrophy or neovascular AMD. The disease has a complex aetiology underlying a mixture of genetic and non-genetic/environmental risk factors that are still incompletely understood. Adding to this complexity is the Alzheimer’s-associated Amyloid beta (A) family of misfolding proteins which accumulate in aged and AMD retinas. The deposition of A within pathogenic deposits under the retina and its dysregulation in plasma of AMD patients offers the possibility of studying degenerative changes in the retina from a new perspective.

Methods: we developed a mouse model of A-induced retinal degeneration in order to study its effects in the living retina. We then exploited a cell culture model to determine its effects at single-cell resolution.

Results: sub-retinally injected human oligomeric A aggregated in murine eyes in a manner consistent with amyloid deposition in donor tissues, and caused progressive retinal degeneration. Two weeks after treatment, A injected eyes showed features similar to neovascular AMD. However, overall retinal function remained unaffected as non-invasive OCT and ERG scans revealed this damage to be highly localised. Studies at single-cell resolution revealed that A was internalised by RPE cells to accumulate within late endosomes and lysosomes. The activity of the lysosomal proteolytic enzyme cathepsin B was upregulated in response to lysosomal A cargos. However, A persisted after cathepsin B activity had returned to baseline levels suggesting a potential new mechanism through which A can accumulate within RPE lysosomes over time. The ability to degrade POS cargos were also diminished in RPE with lysosomal A, revealing an altogether novel cellular mechanism through which A can contribute to AMD.

Conclusions: our findings reveal a novel disease-causing pathway in the senescent retina. They also shed light on how impaired cargo-handling processes including poor responses to the accumulation of aggregate-prone/high-molecular-weight molecules within lysosomes underpin related pathophysiologies such as Alzheimer’s disease. As an unhealthy diet and metabolic disorders are associated with increased A pathology in the eye and brain, our results provide further evidence of shared pathophysiology in these tissues.

Disclosures: none
1387-2877
1037
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Newman, Tracey
322290cb-2e9c-445d-a047-00b1bea39a25
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Cree, Angela
6724b71b-8828-4abb-971f-0856c2af555e
Lee, Helena
5d36fd1e-9334-4db5-b201-034d147133fb
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Newman, Tracey
322290cb-2e9c-445d-a047-00b1bea39a25
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Cree, Angela
6724b71b-8828-4abb-971f-0856c2af555e
Lee, Helena
5d36fd1e-9334-4db5-b201-034d147133fb

Ratnayaka, J. Arjuna, Newman, Tracey, Lotery, Andrew, Cree, Angela and Lee, Helena (2018) Dementia of the Eye- Alzheimer’s-linked Amyloid beta proteins provide new insights into retinal degeneration. Journal of Alzheimer's Disease, 64, 1037. (doi:10.3233/JAD-189006).

Record type: Meeting abstract

Abstract

Purpose: age-related Macular Degeneration (AMD) is the most common cause of irreversible blindness in the developed world for which there is no effective treatment. Advanced stages of the disease manifests as two broadly-defined phenotypes; geographic atrophy or neovascular AMD. The disease has a complex aetiology underlying a mixture of genetic and non-genetic/environmental risk factors that are still incompletely understood. Adding to this complexity is the Alzheimer’s-associated Amyloid beta (A) family of misfolding proteins which accumulate in aged and AMD retinas. The deposition of A within pathogenic deposits under the retina and its dysregulation in plasma of AMD patients offers the possibility of studying degenerative changes in the retina from a new perspective.

Methods: we developed a mouse model of A-induced retinal degeneration in order to study its effects in the living retina. We then exploited a cell culture model to determine its effects at single-cell resolution.

Results: sub-retinally injected human oligomeric A aggregated in murine eyes in a manner consistent with amyloid deposition in donor tissues, and caused progressive retinal degeneration. Two weeks after treatment, A injected eyes showed features similar to neovascular AMD. However, overall retinal function remained unaffected as non-invasive OCT and ERG scans revealed this damage to be highly localised. Studies at single-cell resolution revealed that A was internalised by RPE cells to accumulate within late endosomes and lysosomes. The activity of the lysosomal proteolytic enzyme cathepsin B was upregulated in response to lysosomal A cargos. However, A persisted after cathepsin B activity had returned to baseline levels suggesting a potential new mechanism through which A can accumulate within RPE lysosomes over time. The ability to degrade POS cargos were also diminished in RPE with lysosomal A, revealing an altogether novel cellular mechanism through which A can contribute to AMD.

Conclusions: our findings reveal a novel disease-causing pathway in the senescent retina. They also shed light on how impaired cargo-handling processes including poor responses to the accumulation of aggregate-prone/high-molecular-weight molecules within lysosomes underpin related pathophysiologies such as Alzheimer’s disease. As an unhealthy diet and metabolic disorders are associated with increased A pathology in the eye and brain, our results provide further evidence of shared pathophysiology in these tissues.

Disclosures: none

Text
BON Conference abstracts_2018 - Version of Record
Restricted to Repository staff only
Request a copy

More information

Published date: 20 July 2018

Identifiers

Local EPrints ID: 422618
URI: http://eprints.soton.ac.uk/id/eprint/422618
ISSN: 1387-2877
PURE UUID: 5db2c603-8394-4c35-bb59-0d5093827e00
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938
ORCID for Tracey Newman: ORCID iD orcid.org/0000-0002-3727-9258
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for Helena Lee: ORCID iD orcid.org/0000-0002-2573-9536

Catalogue record

Date deposited: 26 Jul 2018 16:30
Last modified: 22 Nov 2021 03:08

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×