{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:00:48Z","timestamp":1793372448535,"version":"4.5.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD), a neurodegenerative disorder associated with amyloid beta (A\u03b2) plaque deposition, leads to cognitive decline in affected individuals. Vision changes are among the reported symptoms in AD with studies showing both decline in functions performed by the visual system as well as associations between vision loss and cognitive impairment in AD patients. Due to the increasing number of individuals diagnosed with AD and its early impact on vision, we sought to provide an in-depth analysis of how A\u03b2, a primary pathology typically preceding many other AD-associated pathologies, affects visual regions of the brain and how microglia, key immune regulators of the brain\u2019s environment, respond to this AD-like pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Amyloid pathology was examined in histological sections containing the dorsolateral geniculate nucleus (dLGN), and the primary visual cortex (V1), suprachiasmatic nucleus (SCN), and superior colliculus (SC) of 5xFAD mice using thioflavin-S and anti-amyloid staining. Microglia morphology was analyzed in Iba1 antibody-stained sections and phagocytic activity was evaluated with CD68 co-staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that in the pathway for image-forming vision, including the dLGN and V1, there was significant A\u03b2 pathology, shifts in microglial morphology to an amoeboid state, localization of microglia around plaques, and increased Iba1\/CD68 co-labeling. However, in non-image-forming visual brain regions such as the SC and SCN, there was minimal A\u03b2 pathology, ramified microglial morphology, and minimal phagocytic activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Overall, A\u03b2 plaque deposition was related to brain-region-specific differences in microglial responses, indicating that visual brain regions are differentially affected by AD pathology in the 5xFAD mouse model of amyloidosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1824891","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:10:55Z","timestamp":1784095855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Plaque-associated microglial polarization in visual brain regions of the 5xFAD mouse model"],"prefix":"10.3389","volume":"18","author":[{"given":"Shaylah","family":"McCool","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center","place":["Omaha, NE, United States"]},{"name":"Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center","place":["Omaha, NE, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnav","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center","place":["Omaha, NE, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie C.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center","place":["Omaha, NE, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Van Hook","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center","place":["Omaha, NE, United States"]},{"name":"Department of Cellular and Integrative Physiology, University of Nebraska Medical Center","place":["Omaha, NE, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10634","DOI":"10.1038\/s41467-024-54779-w","article-title":"Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer\u2019s Disease.","volume":"15","author":"Balig\u00e1cs","year":"2024","journal-title":"Nat. Commun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4004","DOI":"10.1038\/s41467-021-24241-2","article-title":"Organization of the inputs and outputs of the mouse superior colliculus.","volume":"12","author":"Benavidez","year":"2021","journal-title":"Nat. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.neuroscience.2022.01.029","article-title":"Structural and functional plasticity in the dorsolateral geniculate nucleus of mice following bilateral enucleation.","volume":"488","author":"Bhandari","year":"2022","journal-title":"Neuroscience"},{"key":"B4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/0304-3940(92)90795-9","article-title":"Distribution of amyloid in the brainstem of patients with Alzheimer disease.","volume":"148","author":"Brilliant","year":"1992","journal-title":"Neurosci. Lett."},{"key":"B5","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1146\/annurev-vision-091517-034142","article-title":"Visual function, organization, and development of the mouse superior colliculus.","volume":"4","author":"Cang","year":"2018","journal-title":"Annu. Rev. Vis. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.neuron.2012.07.011","article-title":"Imaging neural activity using Thy1-GCaMP transgenic mice.","volume":"76","author":"Chen","year":"2012","journal-title":"Neuron"},{"key":"B7","doi-asserted-by":"publisher","first-page":"108535","DOI":"10.1016\/j.jneumeth.2019.108535","article-title":"Imaging neuronal activity in the central and peripheral nervous systems using new Thy1.2-GCaMP6 transgenic mouse lines.","volume":"334","author":"Cichon","year":"2020","journal-title":"J. Neurosci. Methods"},{"key":"B8","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.neurobiolaging.2018.03.017","article-title":"The retina as a window to early dysfunctions of Alzheimer\u2019s disease following studies with a 5xFAD mouse model.","volume":"67","author":"Criscuolo","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"B9","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1111\/nan.12249","article-title":"Changes to the lateral geniculate nucleus in Alzheimer\u2019s disease but not dementia with Lewy bodies.","volume":"42","author":"Erskine","year":"2016","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/s0896-6273(00)00084-2","article-title":"Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP.","volume":"28","author":"Feng","year":"2000","journal-title":"Neuron"},{"key":"B11","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/s13195-020-00688-1","article-title":"Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer\u2019s disease mouse model with suppression of glymphatic clearance.","volume":"12","author":"Feng","year":"2020","journal-title":"Alzheimers Res. Ther."},{"key":"B12","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1046\/j.1365-2362.2002.00994.x","article-title":"Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer\u2019s disease brain and damage the blood-brain barrier.","volume":"32","author":"Fiala","year":"2002","journal-title":"Eur. J. Clin. Invest."},{"key":"B13","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/1742-2094-7-61","article-title":"Distinct modulation of microglial amyloid \u03b2 phagocytosis and migration by neuropeptides (i).","volume":"7","author":"Fleisher-Berkovich","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"B14","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s00401-021-02263-w","article-title":"Distinct amyloid-\u03b2 and tau-associated microglia profiles in Alzheimer\u2019s disease.","volume":"141","author":"Gerrits","year":"2021","journal-title":"Acta Neuropathol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e20210542","DOI":"10.1084\/jem.20210542","article-title":"Activated microglia mitigate A\u03b2-associated tau seeding and spreading.","volume":"218","author":"Gratuze","year":"2021","journal-title":"J. Exp. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1126\/science.1190830","article-title":"High-resolution analysis of parent-of-origin allelic expression in the mouse brain.","volume":"329","author":"Gregg","year":"2010","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1152\/jn.00651.2017","article-title":"Development, form, and function of the mouse visual thalamus.","volume":"120","author":"Guido","year":"2018","journal-title":"J. Neurophysiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models.","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.3390\/brainsci11091232","article-title":"Clinical implications of amyloid-beta accumulation in occipital lobes in Alzheimer\u2019s continuum.","volume":"11","author":"Hwang","year":"2021","journal-title":"Brain Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1186\/s40478-016-0399-z","article-title":"Post-mortem histopathology underlying \u03b2-amyloid PET imaging following flutemetamol F 18 injection.","volume":"4","author":"Ikonomovic","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"115052","DOI":"10.1016\/j.celrep.2024.115052","article-title":"Microglia degrade Alzheimer\u2019s amyloid-beta deposits extracellularly via digestive exophagy.","volume":"43","author":"Jacquet","year":"2024","journal-title":"Cell Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3389\/fneur.2016.00055","article-title":"Visual and ocular manifestations of Alzheimer\u2019s disease and their use as biomarkers for diagnosis and progression.","volume":"7","author":"Javaid","year":"2016","journal-title":"Front. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/0039-6257(89)90127-6","article-title":"Ophthalmologic manifestations of Alzheimer\u2019s disease.","volume":"34","author":"Katz","year":"1989","journal-title":"Surv. Ophthalmol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e668","DOI":"10.1111\/aos.13319","article-title":"Visual system manifestations of Alzheimer\u2019s disease.","volume":"95","author":"Kusne","year":"2017","journal-title":"Acta Ophthalmol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4105","DOI":"10.1093\/brain\/awae221","article-title":"Amyloid-\u03b2-activated microglia can induce compound proteinopathies.","volume":"147","author":"Lee","year":"2024","journal-title":"Brain"},{"key":"B26","doi-asserted-by":"publisher","first-page":"109281","DOI":"10.1016\/j.isci.2024.109281","article-title":"The decreased astrocyte-microglia interaction reflects the early characteristics of Alzheimer\u2019s disease.","volume":"27","author":"Liu","year":"2024","journal-title":"iScience"},{"key":"B27","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/j.cell.2016.04.001","article-title":"Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation.","volume":"165","author":"Lui","year":"2016","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e14561","DOI":"10.1002\/alz.14561","article-title":"Visual-somatosensory integration as a novel behavioral marker of amyloid pathology.","volume":"21","author":"Mahoney","year":"2025","journal-title":"Alzheimers Dement."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e0319397","DOI":"10.1371\/journal.pone.0319397","article-title":"Retinal and thalamic alterations in the 5xFAD mouse model of Alzheimer\u2019s disease.","volume":"20","author":"McCool","year":"2025","journal-title":"PLoS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6483","DOI":"10.1074\/jbc.274.10.6483","article-title":"Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.","volume":"274","author":"Moechars","year":"1999","journal-title":"J. Biol. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"13211","DOI":"10.1038\/s41598-017-13581-z","article-title":"Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury.","volume":"7","author":"Morrison","year":"2017","journal-title":"Sci. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s40478-023-01530-z","article-title":"Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer\u2019s disease hippocampus.","volume":"11","author":"Mu\u00f1oz-Castro","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.3390\/cells11233901","article-title":"Mesoscopic mapping of visual pathway in a female 5XFAD mouse model of Alzheimer\u2019s disease.","volume":"11","author":"Nam","year":"2022","journal-title":"Cells"},{"key":"B34","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41582-021-00577-7","article-title":"Circadian rhythms in neurodegenerative disorders.","volume":"18","author":"Nassan","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"B35","doi-asserted-by":"publisher","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.","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"9109","DOI":"10.1038\/s41598-020-66002-z","article-title":"Low vision and the risk of dementia: A nationwide population-based cohort study.","volume":"10","author":"Paik","year":"2020","journal-title":"Sci. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1038\/s41467-017-01150-x","article-title":"Earliest accumulation of \u03b2-amyloid occurs within the default-mode network and concurrently affects brain connectivity.","volume":"8","author":"Palmqvist","year":"2017","journal-title":"Nat. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s12551-023-01052-x","article-title":"Effect of \u03b2-amyloid on blood-brain barrier properties and function.","volume":"15","author":"Petrushanko","year":"2023","journal-title":"Biophys. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"5281829","DOI":"10.1155\/2017\/5281829","article-title":"Trans-Synaptic spread of Amyloid- \u03b2 in Alzheimer\u2019s disease: Paths to \u03b2-Amyloidosis.","volume":"2017","author":"Pignataro","year":"2017","journal-title":"Neural Plast."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e70476","DOI":"10.1002\/alz.70476","article-title":"Ocular changes as potential biomarkers for early diagnosis of Alzheimer\u2019s disease.","volume":"21","author":"Poudel","year":"2025","journal-title":"Alzheimers Dement."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1720382","DOI":"10.3389\/fncel.2025.1720382","article-title":"Unmasking early microglial remodeling in an Alzheimer\u2019s disease mouse model.","volume":"19","author":"Saminathan","year":"2026","journal-title":"Front. Cell Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1016\/j.neuron.2024.12.025","article-title":"Parental origin of transgene modulates amyloid-\u03b2 plaque burden in the 5xFAD mouse model of Alzheimer\u2019s disease.","volume":"113","author":"Sasmita","year":"2025","journal-title":"Neuron"},{"key":"B43","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1146\/annurev-neuro-071714-033842","article-title":"Architecture, function, and assembly of the mouse visual system.","volume":"40","author":"Seabrook","year":"2017","journal-title":"Annu. Rev. Neurosci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.neuron.2018.12.009","article-title":"Layer-Specific physiological features and interlaminar interactions in the primary visual cortex of the mouse.","volume":"101","author":"Senzai","year":"2019","journal-title":"Neuron"},{"key":"B45","doi-asserted-by":"publisher","first-page":"105146","DOI":"10.1016\/j.nbd.2020.105146","article-title":"Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.","volume":"147","author":"Simons","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/ana.24029","article-title":"\u03b2-Amyloid is transmitted via neuronal connections along axonal membranes.","volume":"75","author":"Song","year":"2014","journal-title":"Ann. Neurol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1093\/brain\/aww016","article-title":"Eliminating microglia in Alzheimer\u2019s mice prevents neuronal loss without modulating amyloid-\u03b2 pathology.","volume":"139","author":"Spangenberg","year":"2016","journal-title":"Brain"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1038\/s41467-019-11674-z","article-title":"Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer\u2019s disease model.","volume":"10","author":"Spangenberg","year":"2019","journal-title":"Nat. Commun."},{"key":"B49","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1097\/00005072-199901000-00004","article-title":"Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia.","volume":"58","author":"Stopa","year":"1999","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e0323513","DOI":"10.1371\/journal.pone.0323513","article-title":"Microglia remodeling in the visual thalamus of the DBA\/2J mouse model of glaucoma.","volume":"20","author":"Thompson","year":"2025","journal-title":"PLoS One"},{"key":"B51","doi-asserted-by":"publisher","first-page":"e16275","DOI":"10.1111\/jnc.16275","article-title":"Preferential clustering of microglia and astrocytes around neuritic plaques during progression of Alzheimer\u2019s disease neuropathological changes.","volume":"169","author":"Tsering","year":"2025","journal-title":"J. Neurochem."},{"key":"B52","doi-asserted-by":"publisher","first-page":"964336","DOI":"10.3389\/fnagi.2022.964336","article-title":"Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer\u2019s disease.","volume":"14","author":"Tsui","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"772717","DOI":"10.3389\/fnagi.2021.772717","article-title":"Microglia polarization in Alzheimer\u2019s disease: Mechanisms and a potential therapeutic target.","volume":"13","author":"Wang","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"57648","DOI":"10.3791\/57648","article-title":"Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ.","author":"Young","year":"2018","journal-title":"J. Vis. Exp."},{"key":"B55","doi-asserted-by":"publisher","first-page":"681831","DOI":"10.3389\/fnins.2021.681831","article-title":"Brain and retinal abnormalities in the 5xFAD mouse model of alzheimer\u2019s disease at early stages.","volume":"15","author":"Zhang","year":"2021","journal-title":"Front. Neurosci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s13024-017-0188-6","article-title":"Microglia limit the expansion of \u03b2-amyloid plaques in a mouse model of Alzheimer\u2019s disease.","volume":"12","author":"Zhao","year":"2017","journal-title":"Mol. Neurodegener."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1824891\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:10:56Z","timestamp":1784095856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1824891\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":56,"alternative-id":["10.3389\/fnagi.2026.1824891"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2026.1824891","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]},"article-number":"1824891"}}