A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes
Abstract Background Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in developed societies. AMD coincides with advanced age to which genetic and lifestyle factors contribute additional risks. High levels of the Alzheimer’s-linked Amyloid beta (Aβ) proteins are...
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2025-06-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01784-w |
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| author | Savannah A. Lynn Sudha Priya Soundara Pandi Aida Sanchez-Bretano Anna-Marie Muir Lidia Parker David S. Chatelet Tutte Newall Jennifer A. Scott Eloise Keeling Neil R. Smyth Jay E. Self Andrew J. Lotery Helena Lee J. Arjuna Ratnayaka |
| author_facet | Savannah A. Lynn Sudha Priya Soundara Pandi Aida Sanchez-Bretano Anna-Marie Muir Lidia Parker David S. Chatelet Tutte Newall Jennifer A. Scott Eloise Keeling Neil R. Smyth Jay E. Self Andrew J. Lotery Helena Lee J. Arjuna Ratnayaka |
| author_sort | Savannah A. Lynn |
| collection | DOAJ |
| description | Abstract Background Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in developed societies. AMD coincides with advanced age to which genetic and lifestyle factors contribute additional risks. High levels of the Alzheimer’s-linked Amyloid beta (Aβ) proteins are correlated with aged/AMD retinas. To delineate the role of Aβ in retinopathy from age-related changes, we used transgenic 5xFAD mice in a longitudinal study to recapitulate the aged/AMD Aβ-burden of the human retina. Methods Mice were genotyped to exclude the retinal degeneration alleles Pde6b rd1 , Pde6brd8, Agouti, Tyr and Oca2. Retinas of 5xFAD and wildtype littermates (97 males/females in total) were longitudinally assessed until 15 months using non-invasive retinal scans: multi-focal electroretinography, optokinetic tracking, optical coherence tomography (OCT), colour fundus photography and fluorescein angiography. Mice were killed at 4, 8 and 15 months, and eyes enucleated for analyses by light, confocal and electron microscopy. Results Age-related changes included a gradual decline of retinal activity in all mice. Subretinal/drusen-like deposits increased with age, but, like retinal vessel morphology and vessel integrity, showed no differences between cohorts. Diminished PSD95 levels indicated impaired photoreceptor-bipolar connectivity which correlated with age. Ultrastructural imaging showed increased electron-dense granules and undigested outer segments within retinal pigment epithelial cells with age. 5xFAD pathology included significant weight reduction vs. wildtype/littermates, which were pronounced in females. 8 month old 5xFAD mice had diminished A and B waves, though the age-related decline in wildtype mice abolished these subsequently. Visual acuity/function was also reduced in 14 month 5xFAD eyes. OCT revealed thickened photoreceptor nuclei and inner segments in 8 month 5xFAD retinae. Scrutiny of chorioretinal tissues revealed diminished photoreceptor nuclei in 4 month 5xFAD eyes, though differences were abolished as both cohorts aged. From 8 months onwards, 5xFAD mice possessed fewer bipolar cell nuclei. Conclusions Chronic Aβ exposure led to the earlier development of retinopathy-linked features, the identification of which advances our understanding of how Aβ contributes to multifaceted retinopathies. These were distinguishable from wider age-related changes and non-specific influences of retinal degeneration alleles in 5xFAD mice. Longitudinal analyses revealed sex and age-related limitations and important 3Rs considerations for future studies using 5xFAD mice. |
| format | Article |
| id | doaj-art-d1d4cb09cbc543a89eaea040cb3ce61c |
| institution | DOAJ |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-d1d4cb09cbc543a89eaea040cb3ce61c2025-08-20T03:22:48ZengBMCAlzheimer’s Research & Therapy1758-91932025-06-0117112110.1186/s13195-025-01784-wA longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changesSavannah A. Lynn0Sudha Priya Soundara Pandi1Aida Sanchez-Bretano2Anna-Marie Muir3Lidia Parker4David S. Chatelet5Tutte Newall6Jennifer A. Scott7Eloise Keeling8Neil R. Smyth9Jay E. Self10Andrew J. Lotery11Helena Lee12J. Arjuna Ratnayaka13Clinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonBiomedical Imaging Unit, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonSchool of Biological Sciences, University of Southampton, Southampton General HospitalClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonClinical and Experimental Sciences, Faculty of Medicine, University of SouthamptonAbstract Background Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in developed societies. AMD coincides with advanced age to which genetic and lifestyle factors contribute additional risks. High levels of the Alzheimer’s-linked Amyloid beta (Aβ) proteins are correlated with aged/AMD retinas. To delineate the role of Aβ in retinopathy from age-related changes, we used transgenic 5xFAD mice in a longitudinal study to recapitulate the aged/AMD Aβ-burden of the human retina. Methods Mice were genotyped to exclude the retinal degeneration alleles Pde6b rd1 , Pde6brd8, Agouti, Tyr and Oca2. Retinas of 5xFAD and wildtype littermates (97 males/females in total) were longitudinally assessed until 15 months using non-invasive retinal scans: multi-focal electroretinography, optokinetic tracking, optical coherence tomography (OCT), colour fundus photography and fluorescein angiography. Mice were killed at 4, 8 and 15 months, and eyes enucleated for analyses by light, confocal and electron microscopy. Results Age-related changes included a gradual decline of retinal activity in all mice. Subretinal/drusen-like deposits increased with age, but, like retinal vessel morphology and vessel integrity, showed no differences between cohorts. Diminished PSD95 levels indicated impaired photoreceptor-bipolar connectivity which correlated with age. Ultrastructural imaging showed increased electron-dense granules and undigested outer segments within retinal pigment epithelial cells with age. 5xFAD pathology included significant weight reduction vs. wildtype/littermates, which were pronounced in females. 8 month old 5xFAD mice had diminished A and B waves, though the age-related decline in wildtype mice abolished these subsequently. Visual acuity/function was also reduced in 14 month 5xFAD eyes. OCT revealed thickened photoreceptor nuclei and inner segments in 8 month 5xFAD retinae. Scrutiny of chorioretinal tissues revealed diminished photoreceptor nuclei in 4 month 5xFAD eyes, though differences were abolished as both cohorts aged. From 8 months onwards, 5xFAD mice possessed fewer bipolar cell nuclei. Conclusions Chronic Aβ exposure led to the earlier development of retinopathy-linked features, the identification of which advances our understanding of how Aβ contributes to multifaceted retinopathies. These were distinguishable from wider age-related changes and non-specific influences of retinal degeneration alleles in 5xFAD mice. Longitudinal analyses revealed sex and age-related limitations and important 3Rs considerations for future studies using 5xFAD mice.https://doi.org/10.1186/s13195-025-01784-w5xFADRetinaMouse modelAmyloid beta (Aβ)AgeRetinopathy |
| spellingShingle | Savannah A. Lynn Sudha Priya Soundara Pandi Aida Sanchez-Bretano Anna-Marie Muir Lidia Parker David S. Chatelet Tutte Newall Jennifer A. Scott Eloise Keeling Neil R. Smyth Jay E. Self Andrew J. Lotery Helena Lee J. Arjuna Ratnayaka A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes Alzheimer’s Research & Therapy 5xFAD Retina Mouse model Amyloid beta (Aβ) Age Retinopathy |
| title | A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes |
| title_full | A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes |
| title_fullStr | A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes |
| title_full_unstemmed | A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes |
| title_short | A longitudinal study of the 5xFAD mouse retina delineates Amyloid beta (Aβ)-mediated retinal pathology from age-related changes |
| title_sort | longitudinal study of the 5xfad mouse retina delineates amyloid beta aβ mediated retinal pathology from age related changes |
| topic | 5xFAD Retina Mouse model Amyloid beta (Aβ) Age Retinopathy |
| url | https://doi.org/10.1186/s13195-025-01784-w |
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