{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T14:39:38Z","timestamp":1766587178274,"version":"3.48.0"},"reference-count":74,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["FCT.2022.08133.PTDC"],"award-info":[{"award-number":["FCT.2022.08133.PTDC"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["UID\/00276\/2025"],"award-info":[{"award-number":["UID\/00276\/2025"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT","doi-asserted-by":"publisher","award":["LA\/P\/0059\/2020"],"award-info":[{"award-number":["LA\/P\/0059\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is marked by cognitive decline, and also by retinal degeneration. Having in mind that docosahexaenoic acid (DHA, 22:6n \u2212 3) is a safe, low-cost, and pivotal fatty acid for brain health and sustained cognitive function, this study exploits environmentally friendly non-fish sources as potential dietary supplements enriched with DHA to prevent or reverse AD. Forty 5xFAD transgenic male mice, aged five weeks old, were randomly distributed by five body weight-matched dietary groups (with eight animals each) and fed isocaloric diets based on the AIN-93M standard formulation for rodents for 6 months. Except for the control feed (without supplementation), each diet contained a modified lipidic fraction supplemented with 2% of the following: (1) linseed oil (LSO, rich in alpha-linolenic acid (ALA, 18:3n \u2212 3)); (2) cod liver oil (fish oil, FO, rich in both DHA and eicosapentaenoic acid (EPA, 20:5n \u2212 3)); (3) Schizochytrium sp. microalga oil (Schizo, with 40% of DHA); and (4) commercial DHASCO (DHASCO, with 70% of DHA). The aim of this study was to measure retinal neural layer thickness, calculate ganglion cell layer (GCL) density, and assess retinal injury by means of immunohistochemical staining for \u03b2-amyloid plaques deposition, TAU protein levels, and IBA1, as hallmark features of AD progression, in order to elucidate the effects of different dietary DHA treatments in Alzheimer\u2019s retinas. Although no statistical differences were observed across retinal layer thicknesses depending on the diet (p &gt; 0.05), there was a consistent pattern for slightly increased retinal thickness in 5xFAD mice fed fish oil relative to the others for the measurement of total layers, in general and for the inner segment\/outer segment layer, the outer nuclear layer, the outer plexiform layer, the inner nuclear layer, and the inner plexiform layer, in particular. The ganglion cell layer (GCL) density was increased in 5xFAD mice fed the DHASCO oil diet relative to the control (p &lt; 0.05), suggesting a benefit of DHA supplementation on the number of viable ganglion cells. No positive staining was observed for \u03b2-amyloid plaques deposition or the neuroinflammatory marker, IBA1, corroborating previous findings in human AD retinas. Conversely, the internal retinal layers showed intense TAU immunostaining. Immnunostained TAU area was significantly reduced in 5xFAD mice fed a fish oil diet compared to control (p &lt; 0.05), although the number of TAU-positive cells did not differ across diets (p &gt; 0.05). The retinal protected integrity derived from the benefits of DHA supplementation found, either from fish oil or DHASCO oil, underscores the potential of retinal biomarkers as non-invasive indicators of cognitive decline and overall brain health, opening new avenues for investigating AD pathophysiology in the retina.<\/jats:p>","DOI":"10.3390\/cells15010008","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T14:27:51Z","timestamp":1766586471000},"page":"8","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Retinal Degeneration in Alzheimer\u2019s Disease 5xFAD Mice Fed DHA-Enriched Diets"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4502-667X","authenticated-orcid":false,"given":"M\u00e1rio S.","family":"Pinho","sequence":"first","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6147-5434","authenticated-orcid":false,"given":"Husaifa","family":"Ahfaz","sequence":"additional","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Sandra","family":"Carvalho","sequence":"additional","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1909-4540","authenticated-orcid":false,"given":"Jorge","family":"Correia","sequence":"additional","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-1605","authenticated-orcid":false,"given":"Maria","family":"Sp\u00ednola","sequence":"additional","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Jos\u00e9 M.","family":"Pestana","sequence":"additional","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Narcisa M.","family":"Bandarra","sequence":"additional","affiliation":[{"name":"Divis\u00e3o de Aquacultura, Valoriza\u00e7\u00e3o e Bioprospe\u00e7\u00e3o (DivAV), Instituto Portugu\u00eas do Mar e da Atmosfera (IPMA, I.P.), Avenida Alfredo Magalh\u00e3es Ramalho, 6, 1495-165 Alg\u00e9s, Portugal"},{"name":"CIIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Universidade do Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6755-4572","authenticated-orcid":false,"given":"Paula A.","family":"Lopes","sequence":"additional","affiliation":[{"name":"CIISA\u2014Centro de Investiga\u00e7\u00e3o Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterin\u00e1ria, Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Laborat\u00f3rio Associado para Ci\u00eancia Animal e Veterin\u00e1ria (AL4AnimalS), Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e581","DOI":"10.1111\/aos.12374","article-title":"Detection of retinal nerve fiber layer degeneration in patients with Alzheimer\u2019s disease using optical coherence tomography: Searching new biomarkers","volume":"92","author":"Bambo","year":"2014","journal-title":"Acta Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5416","DOI":"10.1007\/s12035-018-1461-6","article-title":"The retina as a window or mirror of the brain changes detected in Alzheimer\u2019s disease: Critical aspects to unravel","volume":"56","author":"Chiquita","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2012.10.002","article-title":"The neuronal organization of the retina","volume":"76","author":"Masland","year":"2012","journal-title":"Neuron"},{"key":"ref_4","unstructured":"Pawlina, W. (2019). Histology. A Text and Atlas: With Correlated Cell and Molecular Biology, Wolters Kluver Health. [8th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"108440","DOI":"10.1016\/j.pharmthera.2023.108440","article-title":"The essential role of docosahexaenoic acid and its derivatives for retinal integrity","volume":"247","author":"Swinkels","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"172801","DOI":"10.1155\/2015\/172801","article-title":"Omega-3 fatty acids in early prevention of inflammatory neurodegenerative disease: A focus on Alzheimer\u2019s disease","volume":"2015","author":"Thomas","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12974-016-0525-7","article-title":"Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer\u2019s disease","volume":"13","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"L\u00e9tondor, A., Buaud, B., Vaysse, C., Richard, E., Lay\u00e9, S., Pallet, V., and Alfos, S. (2016). EPA\/DHA and vitamin A supplementation improves spatial memory and alleviates the age-related decrease in hippocampal RXR\u03b3 and kinase expression in rats. Front. Aging Neurosci., 8.","DOI":"10.3389\/fnagi.2016.00103"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"P\u00e1dua, M.S., Guil-Guerrero, J.L., and Lopes, P.A. (2024). Behaviour hallmarks in Alzheimer\u2019s disease 5xFAD mouse model. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126766"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"P\u00e1dua, M.S., Guil-Guerrero, J.L., Prates, J.A.M., and Lopes, P.A. (2024). Insights on the use of transgenic mice models in Alzheimer\u2019s disease research. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052805"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: Potential factors in amyloid plaque formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13024-017-0231-7","article-title":"Practical considerations for choosing a mouse model of Alzheimer\u2019s disease","volume":"12","author":"Jankowsky","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ayabe, T., and Ano, Y. (2020). Alzheimer model 5xfad mice and applications to dementia: Transgenic mouse models, a focus on neuroinflammation, microglia, and food-derived components. Genetics, Neurology, Behavior, and Diet in Dementia, Academic Press.","DOI":"10.1016\/B978-0-12-815868-5.00052-9"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ismeurt, C., Giannoni, P., and Claeysen, S. (2020). The 5XFAD mouse model of Alzheimer\u2019s disease. Diagnosis and Management in Dementia, Academic Press.","DOI":"10.1016\/B978-0-12-815854-8.00013-6"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lee, S., Jiang, K., McIlmoyle, B., To, E., Qinyuan, A.X., Hirsch-Reinshagen, V., Mackenzie, I.R., Hsiung, G.-Y.R., Eadie, B.D., and Sarunic, M.V. (2020). Amyloid Beta immunoreactivity in the retinal ganglion cell layer of the Alzheimer\u2019s eye. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00758"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-de-Eguileta, A., Cerver\u00f3, A., Ruiz de Sabando, A., S\u00e1nchez-Juan, P., and Casado, A. (2020). Ganglion cell layer thinning in Alzheimer\u2019s disease. Medicina, 56.","DOI":"10.3390\/medicina56100553"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/0006-8993(89)90653-7","article-title":"Retinal ganglion cell degeneration in Alzheimer\u2019s disease","volume":"501","author":"Blanks","year":"1989","journal-title":"Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"La Morgia, C., Ross-Cisneros, F.N., Sadun, A.A., and Carelli, V. (2017). Retinal ganglion cells and circadian rhythms in Alzheimer\u2019s disease, Parkinson\u2019s disease, and beyond. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00162"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/s40478-020-01094-2","article-title":"Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer\u2019s disease","volume":"8","author":"Bevan","year":"2020","journal-title":"Acta Neuropathol. Comm."},{"key":"ref_20","unstructured":"Van Zutphen, L.F.M., Baumans, V., and Beynen, A.C. (2001). Principles of Laboratory Animal Science: A Contribution to the Humane Use and Care of Animals and to the Quality of Experimental Results, Elsevier Ltd.. [2nd ed.]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipids from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/j.1365-2621.1997.tb04364.x","article-title":"Seasonal changes in lipid composition of sardine (Sardina pilchardus)","volume":"62","author":"Bandarra","year":"1997","journal-title":"J. Food Sci."},{"key":"ref_23","unstructured":"Curran, S. (2020). Staining and quantification of \u03b2-amyloid pathology in transgenic mouse models of Alzheimer\u2019s disease. Aging: Methods and Protocols, Humana Press. Chapter 19."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"de Mello-Sampayo, C., P\u00e1dua, M.S., Silva, M.R., Louren\u00e7o, M., Pinto, R.M.A., Carvalho, S., Correia, J., Martins, C.F., Gomes, R., and Gomes-Bispo, A. (2025). Neuronal count, brain injury, and sustained cognitive function in 5\u00d7FAD Alzheimer\u2019s disease mice fed DHA-enriched diets. Biomolecules, 15.","DOI":"10.3390\/biom15081164"},{"key":"ref_25","unstructured":"SAS\/STAT (2004). SAS User\u2019s Guide, Version 9.1, SAS Institute."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ashok, A., Singh, N., Chaudhary, S., Bellamkonda, V., Kritikos, A.E., Wise, A.S., Rana, N., McDonald, D., and Ayyagari, R. (2020). Retinal degeneration and Alzheimer\u2019s disease: An evolving link. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197290"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhang, M., Zhong, L., Han, X., Xiong, G., Xu, D., Zhang, S., Cheng, H., Chiu, K., and Xu, Y. (2021). Brain and retinal abnormalities in the 5xFAD mouse model of Alzheimer\u2019s disease at early stages. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.681831"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41746-024-01292-5","article-title":"Early detection of dementia through retinal imaging and trustworthy AI","volume":"7","author":"Hao","year":"2024","journal-title":"npj Digit. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102229","DOI":"10.1016\/j.redox.2022.102229","article-title":"Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer\u2019s disease mice model","volume":"50","author":"Tang","year":"2022","journal-title":"Redox Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1750-1326-8-2","article-title":"Neuron loss in the 5XFAD mouse model of Alzheimer\u2019s disease correlates with intraneuronal A\u03b242 accumulation and caspase-3 activation","volume":"8","author":"Eimer","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"781","DOI":"10.3233\/JAD-2012-120982","article-title":"Evidence for early cognitive impairment related to frontal cortex in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"33","author":"Girard","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41598-018-19699-y","article-title":"Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer\u2019s disease mouse model 5xFAD","volume":"8","author":"Yang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41597-021-01054-y","article-title":"Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer\u2019s disease","volume":"8","author":"Forner","year":"2021","journal-title":"Sci. Data"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kang, E.Y., Liu, P.-K., Wen, Y.-T., Quinn, P.M.J., Levi, S.R., Wang, N.-K., and Tsai, R.-K. (2021). Role of oxidative stress in ocular diseases associated with retinal ganglion cells degeneration. Antioxidants, 10.","DOI":"10.3390\/antiox10121948"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104502","DOI":"10.1016\/j.jfca.2022.104502","article-title":"Seasonal variation of chub mackerel (Scomber colias) selenium and vitamin B12 content and its potential role in human health","volume":"109","author":"Rego","year":"2022","journal-title":"J. Food Comp. Analys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/ajcn\/83.2.191","article-title":"The acute and chronic toxic effects of vitamin A","volume":"83","author":"Penniston","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Carazo, A., Mac\u00e1kov\u00e1, K., Matou\u0161ov\u00e1, K., Kr\u010dmov\u00e1, L.K., Protti, M., and Mlad\u011bnka, P. (2021). Vitamin A update: Forms, sources, kinetics, detection, function, deficiency, therapeutic use and toxicity. Nutrients, 13.","DOI":"10.3390\/nu13051703"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ophtha.2020.08.018","article-title":"AREDS and AREDS2 Research Groups. Dietary nutrient intake and progression to late age-related macular degeneration in the age-related eye disease studies 1 and 2","volume":"128","author":"Mares","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1136\/jnnp-2020-325347","article-title":"Retinal imaging in Alzheimer\u2019s disease","volume":"92","author":"Cheung","year":"2021","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e001061","DOI":"10.1136\/bmjophth-2022-001061","article-title":"Total retinal thickness: A neglected factor in the evaluation of inner retinal thickness","volume":"7","author":"Banghart","year":"2022","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e202300003","DOI":"10.1002\/tbio.202300003","article-title":"Ratiometric analysis of in vivo optical coherence tomography retinal layer thicknesses for detection of changes in Alzheimer\u2019s disease","volume":"5","author":"Sharma","year":"2023","journal-title":"Transl. Biophotonics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s00401-016-1613-6","article-title":"Ocular indicators of Alzheimer\u2019s: Exploring disease in the retina","volume":"132","author":"Hart","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e93621","DOI":"10.1172\/jci.insight.93621","article-title":"Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer\u2019s disease","volume":"2","author":"Koronyo","year":"2017","journal-title":"JCI Insight"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Mirzaei, N., Shi, H., Oviatt, M., Doustar, J., Rentsendorj, A., Fuchs, D.T., Sheyn, J., Black, K.L., Koronyo, Y., and Koronyo-Hamaoui, M. (2020). Alzheimer\u2019s retinopathy: Seeing disease in the eyes. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00921"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s40478-022-01448-y","article-title":"M\u00fcller cell degeneration and microglial dysfunction in the Alzheimer\u2019s retina","volume":"10","author":"Xu","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101273","DOI":"10.1016\/j.preteyeres.2024.101273","article-title":"Alzheimer\u2019s disease pathophysiology in the Retina","volume":"101","author":"Gaire","year":"2024","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1002\/glia.24514","article-title":"ER-stress response in retinal M\u00fcller glia occurs significantly earlier than amyloid pathology in the Alzheimer\u2019s mouse brain and retina","volume":"72","author":"Palko","year":"2024","journal-title":"Glia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/bpa.12070","article-title":"Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer\u2019s and Parkinson\u2019s disease patients","volume":"24","author":"Ho","year":"2014","journal-title":"Brain Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1093\/jnen\/nlx020","article-title":"Absence of Alzheimer disease neuropathologic changes in eyes of subjects with Alzheimer disease","volume":"76","author":"Williams","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sch\u00f6n, C., Hoffmann, N.A., Ochs, S.M., Burgold, S., Filser, S., Steinbach, S., Seeliger, M.W., Arzberger, T., Goedert, M., and Kretzschmar, H.A. (2012). Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0053547"},{"key":"ref_51","first-page":"162","article-title":"Retinal thickness in Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"6","author":"Verbraak","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Grimaldi, A., Pediconi, N., Oieni, F., Pizzarelli, R., Rosito, M., Giubettini, M., Santini, T., Limatola, C., Ruocco, G., and Ragozzino, D. (2019). Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer\u2019s disease patients, possible biomarkers for early diagnosis. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00925"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"pgac164","DOI":"10.1093\/pnasnexus\/pgac164","article-title":"Label-free hyperspectral imaging and deep-learning prediction of retinal amyloid \u03b2-protein and phosphorylated tau","volume":"1","author":"Du","year":"2022","journal-title":"PNAS Nexus"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s00401-022-02525-1","article-title":"Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer\u2019s disease and primary tauopathies","volume":"145","author":"Morrema","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13195-023-01375-7","article-title":"The fluorescent ligand bTVBT2 reveals increased p-tau uptake by retinal microglia in Alzheimer\u2019s disease patients and AppNL-F\/NL-F mice","volume":"16","author":"Andersson","year":"2024","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00401-024-02760-8","article-title":"Identification of retinal tau oligomers, citrullinated tau, and other tau isoforms in early and advanced AD and relations to disease status","volume":"148","author":"Shi","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/alz.13424","article-title":"Primary retinal tauopathy: A tauopathy with a distinct molecular pattern","volume":"20","author":"Walkiewicz","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4572","DOI":"10.1002\/alz.13008","article-title":"Detection of early proteomic alterations in 5xFAD Alzheimer\u2019s disease neonatal mouse model via MALDI-MSI","volume":"19","author":"Uras","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Oblak, A.L., Lin, P.B., Kotredes, K.P., Pandey, R.S., Garceau, D., Williams, H.M., Uyar, A., O\u2019Rourke, R., O\u2019Rourke, S., and Ingraham, C. (2021). Comprehensive evaluation of the 5XFAD mouse model for preclinical testing applications: A MODEL-AD study. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.713726"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1038\/s41598-021-81304-6","article-title":"Thioflavin-positive tau aggregates complicating quantification of amyloid plaques in the brain of 5XFAD transgenic mouse model","volume":"11","author":"Shin","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13195-018-0459-7","article-title":"Prevalence and risk of progression of preclinical Alzheimer\u2019s disease stages: A systematic review and meta-analysis","volume":"11","author":"Parnetti","year":"2019","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s00401-023-02548-2","article-title":"Retinal pathological features and proteome signatures of Alzheimer\u2019s disease","volume":"145","author":"Koronyo","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0197-4580(96)00009-7","article-title":"Retinal pathology in Alzheimer\u2019s disease. II. Regional neuron loss and glial changes in GCL","volume":"17","author":"Blanks","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"26039","DOI":"10.31083\/JIN26039","article-title":"The role of the ganglion cell layer as an OCT biomarker in neurodegenerative diseases","volume":"24","author":"Ruggeri","year":"2025","journal-title":"J. Integr. Neurosci."},{"key":"ref_65","first-page":"285","article-title":"Ganglion cell distribution in the retina of the mouse","volume":"20","author":"Olsen","year":"1981","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1177\/0192623320976375","article-title":"Mammalian retinal cell quantification","volume":"49","author":"Muthuswamy","year":"2020","journal-title":"Toxicol. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Claes, M., and Moons, L. (2022). Retinal ganglion cells: Global number, density and vulnerability to Glaucomatous injury in common laboratory mice. Cells, 11.","DOI":"10.3390\/cells11172689"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5953","DOI":"10.1167\/iovs.13-12046","article-title":"Evaluation of retinal nerve fiber layer and ganglion cell layer thickness in Alzheimer\u2019s disease using Spectral-Domain Optical Coherence Tomography","volume":"54","author":"Marziani","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_69","first-page":"570","article-title":"Ganglion cell layer thinning in prodromal Alzheimer\u2019s disease defined by amyloid PET","volume":"5","author":"Lage","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1001\/jamaophthalmol.2021.6082","article-title":"Associations between retinal nerve fiber layer and ganglion cell layer in middle age and cognition from childhood to adulthood","volume":"140","author":"Ambler","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source Platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Beretta, C.A., Liu, S., Stegemann, A., Gan, Z., Wang, L., Linette, L.T., and Kuner, R. (2023). Quanty-cFOS, a novel ImageJ\/Fiji algorithm for automated counting of immunoreactive cells in tissue sections. Cells, 12.","DOI":"10.3390\/cells12050704"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"469","DOI":"10.14283\/jpad.2023.118","article-title":"Beyond vision: A view from eye to Alzheimer\u2019s disease and dementia","volume":"11","author":"Zheng","year":"2024","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"592S","DOI":"10.3945\/jn.111.155259","article-title":"Mechanisms of action of (n-3) fatty acids","volume":"142","author":"Calder","year":"2012","journal-title":"J. Nutr."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/1\/8\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T14:37:31Z","timestamp":1766587051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/1\/8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15010008"],"URL":"https:\/\/doi.org\/10.3390\/cells15010008","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,19]]}}}