Oligomeric Aβ<sub>1-42</sub> 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 Aβ<sub>1-42</sub>, wh...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/10/2/413 |
| _version_ | 1797396349074800640 |
|---|---|
| author | Savannah A. Lynn David A. Johnston Jenny A. Scott Rosie Munday Roshni S. Desai Eloise Keeling Ruaridh Weaterton Alexander Simpson Dillon Davis Thomas Freeman David S. Chatelet Anton Page Angela J. Cree Helena Lee Tracey A. Newman Andrew J. Lotery J. Arjuna Ratnayaka |
| author_facet | Savannah A. Lynn David A. Johnston Jenny A. Scott Rosie Munday Roshni S. Desai Eloise Keeling Ruaridh Weaterton Alexander Simpson Dillon Davis Thomas Freeman David S. Chatelet Anton Page Angela J. Cree Helena Lee Tracey A. Newman Andrew J. Lotery J. Arjuna Ratnayaka |
| author_sort | Savannah A. Lynn |
| collection | DOAJ |
| description | 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 Aβ<sub>1-42</sub>, 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 lysosomes 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. |
| first_indexed | 2024-03-09T00:49:57Z |
| format | Article |
| id | doaj.art-d442198e469c40d1a0b5154e1a50840f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T00:49:57Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d442198e469c40d1a0b5154e1a50840f2023-12-11T17:18:13ZengMDPI AGCells2073-44092021-02-0110241310.3390/cells10020413Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE FunctionSavannah A. Lynn0David A. Johnston1Jenny A. Scott2Rosie Munday3Roshni S. Desai4Eloise Keeling5Ruaridh Weaterton6Alexander Simpson7Dillon Davis8Thomas Freeman9David S. Chatelet10Anton Page11Angela J. Cree12Helena Lee13Tracey A. Newman14Andrew J. Lotery15J. Arjuna Ratnayaka16Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKBiomedical Imaging Unit, University of Southampton, MP12, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKBiomedical Imaging Unit, University of Southampton, MP12, Tremona Road, Southampton SO16 6YD, UKBiomedical Imaging Unit, University of Southampton, MP12, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, MP 806, Tremona Road, Southampton SO16 6YD, UKAlzheimer’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 Aβ<sub>1-42</sub>, 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 lysosomes 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.https://www.mdpi.com/2073-4409/10/2/413retinal pigment epithelium (RPE)amyloid beta (Aβ)age-related macular degeneration (AMD)agingautophagy–lysosomal pathwaysight loss |
| spellingShingle | Savannah A. Lynn David A. Johnston Jenny A. Scott Rosie Munday Roshni S. Desai Eloise Keeling Ruaridh Weaterton Alexander Simpson Dillon Davis Thomas Freeman David S. Chatelet Anton Page Angela J. Cree Helena Lee Tracey A. Newman Andrew J. Lotery J. Arjuna Ratnayaka Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function Cells retinal pigment epithelium (RPE) amyloid beta (Aβ) age-related macular degeneration (AMD) aging autophagy–lysosomal pathway sight loss |
| title | Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function |
| title_full | Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function |
| title_fullStr | Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function |
| title_full_unstemmed | Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function |
| title_short | Oligomeric Aβ<sub>1-42</sub> Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function |
| title_sort | oligomeric aβ sub 1 42 sub induces an amd like phenotype and accumulates in lysosomes to impair rpe function |
| topic | retinal pigment epithelium (RPE) amyloid beta (Aβ) age-related macular degeneration (AMD) aging autophagy–lysosomal pathway sight loss |
| url | https://www.mdpi.com/2073-4409/10/2/413 |
| work_keys_str_mv | AT savannahalynn oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT davidajohnston oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT jennyascott oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT rosiemunday oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT roshnisdesai oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT eloisekeeling oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT ruaridhweaterton oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT alexandersimpson oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT dillondavis oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT thomasfreeman oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT davidschatelet oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT antonpage oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT angelajcree oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT helenalee oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT traceyanewman oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT andrewjlotery oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction AT jarjunaratnayaka oligomericabsub142subinducesanamdlikephenotypeandaccumulatesinlysosomestoimpairrpefunction |