{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:38:57Z","timestamp":1787027937052,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China's Major Projects for Science and Technology Innovation 2030","award":["2022ZD0208503"],"award-info":[{"award-number":["2022ZD0208503"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Visual dysfunction emerges during the mild cognitive impairment stage of early Alzheimer\u2019s disease (AD). While previous studies have primarily focused on retinal pathology, the early pathological progression across central nodes of the visual pathway remains inadequately characterized. This study examined regional pathological and structural alterations throughout the visual pathway at different disease stages in APP\/PS1 transgenic mice aged 3, 6, and 9 months. Methods: Cognitive function was first assessed using novel object recognition and Y-maze tests to stage disease progression. Subsequently, Histological staining was employed to systematically analyze pathological features in the retina, lateral geniculate nucleus (LGN), and primary visual cortex (V1). Evaluated parameters encompassed \u03b2-amyloid (A\u03b2) deposition levels, microglial activation status, total neuronal counts, parvalbumin (PV)-positive neuron numbers, and tissue thickness measurements of the retina and V1. Results: At 6 months, mice exhibited an early symptomatic phenotype with selective spatial working memory deficits while long-term memory remained intact. Pathological analysis revealed concurrent A\u03b2 deposition and microglial activation in V1, retina, and hippocampus by 6 months, whereas comparable LGN changes manifested only at 9 months, demonstrating regional heterogeneity in disease progression. V1 neuronal populations remained stable through 6 months but showed significant reduction by 9 months, though PV-positive neurons were selectively preserved. The LGN exhibited no neuronal loss even at 9 months. Gross structural thickness of both retina and V1 remained unchanged across all timepoints. Conclusions: These findings demonstrate that early visual system pathology in this AD model extends beyond the retina. The primary visual cortex exhibits early pathological changes (A\u03b2 deposition and neuroinflammation) concurrent with hippocampal involvement, progressing to selective neuronal loss in later stages. The severity and selectivity of V1 pathology surpass those observed in other visual pathway nodes, including the LGN. Thus, V1 could represent not merely an affected region but a promising site for elucidating early cortical AD mechanisms and developing novel diagnostic biomarkers.<\/jats:p>","DOI":"10.3390\/diagnostics15212768","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:55:22Z","timestamp":1762178122000},"page":"2768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pathological and Structural Alterations of the Visual Pathway in APP\/PS1 Mice: A Spatiotemporal Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Jingan","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China"},{"name":"Research Unit of NeuroInformation (2019RU035), Chinese Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"MOE Key Lab for NeuroInformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xia","sequence":"additional","affiliation":[{"name":"Research Unit of NeuroInformation (2019RU035), Chinese Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"MOE Key Lab for NeuroInformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences, Medical School, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Chen","sequence":"additional","affiliation":[{"name":"Research Unit of NeuroInformation (2019RU035), Chinese Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"MOE Key Lab for NeuroInformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences, Medical School, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezhong","family":"Yao","sequence":"additional","affiliation":[{"name":"Research Unit of NeuroInformation (2019RU035), Chinese Academy of Medical Sciences, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"MOE Key Lab for NeuroInformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China"},{"name":"Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Sichuan Academy of Medical Sciences, Medical School, University of Electronic Science and Technology of China, Chengdu 610072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","unstructured":"Alzheimer\u2019s Disease International (2025, August 03). World Alzheimer Report 2024. Global Changes in Attitudes to Dementia.. Available online: https:\/\/www.alzint.org\/resource\/world-alzheimer-report-2024\/."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Salobrar-Garc\u00eda, E., de Hoz, R., Ram\u00edrez, A.I., L\u00f3pez-Cuenca, I., Rojas, P., Vazirani, R., Amarante, C., Yubero, R., Gil, P., and Pinazo-Dur\u00e1n, M.D. (2019). Changes in visual function and retinal structure in the progression of Alzheimer\u2019s disease. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220535"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/eye.2017.23","article-title":"Visual dysfunction and its correlation with retinal changes in patients with Alzheimer\u2019s disease","volume":"31","author":"Polo","year":"2017","journal-title":"Eye"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Begde, A., Wilcockson, T., Brayne, C., and Hogervorst, E. (2024). Visual processing speed and its association with future dementia development in a population-based prospective cohort: EPIC-Norfolk. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-55637-x"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13024-024-00776-y","article-title":"Aging-associated sensory decline and Alzheimer\u2019s disease","volume":"19","author":"Hong","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Alvite-Pi\u00f1eiro, T., L\u00f3pez-L\u00f3pez, M., Regueiro, U., P\u00edas-Peleteiro, J.M., Sobrino, T., and Lema, I. (2025). Visual Function in Alzheimer\u2019s Disease: Current Understanding and Potential Mechanisms Behind Visual Impairment. J. Clin. Med., 14.","DOI":"10.3390\/jcm14175963"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40035-021-00230-9","article-title":"Advances in retina imaging as potential biomarkers for early diagnosis of Alzheimer\u2019s disease","volume":"10","author":"Zhang","year":"2021","journal-title":"Transl. Neurodegener."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/jir.13214","article-title":"Eye tracking as a tool for detecting Alzheimer\u2019s disease in people with Down syndrome","volume":"69","author":"Kovacs","year":"2025","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_9","doi-asserted-by":"crossref","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":"Alzheimer\u2019s Dement."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2147\/EB.S516393","article-title":"Recent Advances in Visual Dysfunction and Ocular Biomarkers in Neurological Disorders","volume":"17","author":"Cheng","year":"2025","journal-title":"Eye Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101590","DOI":"10.1016\/j.arr.2022.101590","article-title":"The retina: A window in which to view the pathogenesis of Alzheimer\u2019s disease","volume":"77","author":"Zhang","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S204","DOI":"10.1016\/j.neuroimage.2010.06.020","article-title":"Identification of amyloid plaques in retinas from Alzheimer\u2019s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model","volume":"54","author":"Koronyo","year":"2011","journal-title":"Neuroimage"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/eye.2015.158","article-title":"How strong is the relationship between glaucoma, the retinal nerve fibre layer, and neurodegenerative diseases such as Alzheimer\u2019s disease and multiple sclerosis?","volume":"29","author":"Hammond","year":"2015","journal-title":"Eye"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1167\/iovs.12-10827","article-title":"The aging eye: Common degenerative mechanisms between the Alzheimer\u2019s brain and retinal disease","volume":"54","author":"Sivak","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1001\/jamaneurol.2018.1578","article-title":"Association of Retinal Nerve Fiber Layer Thinning with Current and Future Cognitive Decline: A Study Using Optical Coherence Tomography","volume":"75","author":"Ko","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1001\/jamaneurol.2018.1563","article-title":"Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: A Population-Based Study","volume":"75","author":"Mutlu","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_17","first-page":"405","article-title":"Perifovea retinal thickness as an ophthalmic biomarker for mild cognitive impairment and early Alzheimer\u2019s disease","volume":"11","author":"Tao","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1007\/s00417-017-3715-9","article-title":"OCT in Alzheimer\u2019s disease: Thinning of the RNFL and superior hemiretina","volume":"255","author":"Cunha","year":"2017","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40035-019-0170-z","article-title":"A longitudinal assessment of retinal function and structure in the APP\/PS1 transgenic mouse model of Alzheimer\u2019s disease","volume":"8","author":"Georgevsky","year":"2019","journal-title":"Transl. Neurodegener."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/j.1365-2990.1995.tb01078.x","article-title":"Pathology of subcortical visual centres in relation to cortical degeneration in Alzheimer\u2019s disease","volume":"21","author":"Leuba","year":"1995","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","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":"ref_22","doi-asserted-by":"crossref","unstructured":"McCool, S., Smith, J.C., Sladek, A., Fan, S., and Van Hook, M.J. (2025). Retinal and thalamic alterations in the 5xFAD mouse model of Alzheimer\u2019s disease. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0319397"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/ncomms1783","article-title":"Staged decline of neuronal function in vivo in an animal model of Alzheimer\u2019s disease","volume":"3","author":"Grienberger","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41398-022-02024-7","article-title":"Neuronal hyperexcitability in Alzheimer\u2019s disease: What are the drivers behind this aberrant phenotype?","volume":"12","author":"Matosin","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1126\/science.1162844","article-title":"Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer\u2019s disease","volume":"321","author":"Busche","year":"2008","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.cell.2012.02.046","article-title":"Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model","volume":"149","author":"Verret","year":"2012","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nature11312","article-title":"Activation of specific interneurons improves V1 feature selectivity and visual perception","volume":"488","author":"Lee","year":"2012","journal-title":"Nature"},{"key":"ref_28","first-page":"55718","article-title":"Novel Object Recognition Test for the Investigation of Learning and Memory in Mice","volume":"126","author":"Lueptow","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1177\/0271678X21996177","article-title":"Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction","volume":"41","author":"Huo","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/cns.13779","article-title":"Ketogenic diet ameliorates cognitive impairment and neuroinflammation in a mouse model of Alzheimer\u2019s disease","volume":"28","author":"Xu","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1523\/JNEUROSCI.1136-17.2017","article-title":"Microglia-Mediated Synapse Loss in Alzheimer\u2019s Disease","volume":"38","author":"Rajendran","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"801","DOI":"10.3233\/JAD-2012-120151","article-title":"Novel object recognition as a facile behavior test for evaluating drug effects in A\u03b2PP\/PS1 Alzheimer\u2019s disease mouse model","volume":"31","author":"Zhang","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nature20587","article-title":"Gamma frequency entrainment attenuates amyloid load and modifies microglia","volume":"540","author":"Iaccarino","year":"2016","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/bpa.12785","article-title":"Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer\u2019s mice and patients","volume":"30","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1007\/s00429-014-0771-3","article-title":"Interneurons, tau and amyloid-\u03b2 in the piriform cortex in Alzheimer\u2019s disease","volume":"220","year":"2015","journal-title":"Brain Struct. Funct."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41386-020-0778-9","article-title":"Parvalbumin interneuron vulnerability and brain disorders","volume":"46","author":"Ruden","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41380-024-02756-6","article-title":"Fast-spiking parvalbumin-positive interneurons: New perspectives of treatment and future challenges in dementia","volume":"30","author":"Zhang","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Tweedy, C., Kindred, N., Curry, J., Williams, C., Taylor, J.P., Atkinson, P., Randall, F., Erskine, D., Morris, C.M., and Reeve, A.K. (2021). Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein. Neurobiol. Dis., 149.","DOI":"10.1016\/j.nbd.2020.105226"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41386-022-01435-w","article-title":"Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in Alzheimer\u2019s disease","volume":"48","author":"Shu","year":"2023","journal-title":"Neuropsychopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4954","DOI":"10.1038\/s41380-023-02168-y","article-title":"Fast-spiking parvalbumin-positive interneurons in brain physiology and Alzheimer\u2019s disease","volume":"28","author":"Hijazi","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3380","DOI":"10.1038\/s41380-019-0483-4","article-title":"Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer\u2019s disease","volume":"25","author":"Hijazi","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/j.cell.2025.02.007","article-title":"Peripheral nervous system microglia-like cells regulate neuronal soma size throughout evolution","volume":"188","author":"Wu","year":"2025","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Henstridge, C.M., Tzioras, M., and Paolicelli, R.C. (2019). Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration. Front. Cell Neurosci., 13.","DOI":"10.3389\/fncel.2019.00063"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/intimm\/dxaa077","article-title":"Neural circuit repair after central nervous system injury","volume":"33","author":"Tsujioka","year":"2021","journal-title":"Int. Immunol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/21\/2768\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:14:13Z","timestamp":1762319653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/21\/2768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":44,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["diagnostics15212768"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15212768","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}