{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:21:28Z","timestamp":1768512088049,"version":"3.49.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"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:p>\n                    Alzheimer\u2019s disease (AD) is characterized by the accumulation of misfolded proteins that trigger neuroinflammation and neuronal loss. The retina, as an extension of the central nervous system, mirrors these pathological processes and represents a potential biomarker. Microglial activation, a key component of neuroinflammation, can be morphologically assessed through automated image analysis. This study performed a quantitative and morphological analysis of retinal microglia in the APP\n                    <jats:sup>NL-F\/NL-F<\/jats:sup>\n                    mouse model of AD across aging (6\u201320\u202fmonths) and comparing them with age-matched C57BL\/6\u202fJ controls using an automated image analysis software. A cross-sectional design was applied to 72 mice (36 APP\n                    <jats:sup>NL-F\/NL-F<\/jats:sup>\n                    and 36 WT). Retinas samples were processed by Iba-1 immunohistochemistry. Quantified parameters included cell number, soma size, arborization area, skeletonization, fluorescence intensity, and Feret\u2019s Diameter Ratio across OS, OPL, IPL, and NFL\/GCL layers. Image analysis was performed using a custom automated system, called MorphoSomas, specifically developed for the comprehensive morphological assessment of microglia. Age-dependent changes were observed in both groups. WT mice showed a later and more gradual activation pattern, whereas APP\n                    <jats:sup>NL-F\/NL-F<\/jats:sup>\n                    mice exhibited early activation from 6\u202fmonths, characterized by increased cell number and soma size, followed by reductions in arborization and skeletonization, indicating progressive activation. The automated system allowed precise and reproducible assessment, highlighting significant differences between groups and retinal layers. In conclusion, retinal microglia in APP\n                    <jats:sup>NL-F\/NL-F<\/jats:sup>\n                    mice exhibit early and biphasic activation followed by signs of dysfunction, reflecting AD neuropathology. Automated analysis enhances objectivity and efficiency in morphological studies. These findings support the retina as a promising, non-invasive biomarker for early AD detection.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2025.1712480","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:26:43Z","timestamp":1768458403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Early and progressive retinal microglial changes in APPNL-F\/NL-F mouse model of Alzheimer\u2019s disease revealed by an automated image analysis software"],"prefix":"10.3389","volume":"17","author":[{"given":"Lidia","family":"S\u00e1nchez-Puebla","sequence":"first","affiliation":[{"name":"Ramon Castroviejo Institute for Ophthalmic Research, Complutense University of Madrid","place":["Madrid, Spain"]},{"name":"Health Research Institute of the Hospital Cl\u00ednico San Carlos (IdISSC)","place":["Madrid, Spain"]},{"name":"Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"L\u00f3pez-Cuenca","sequence":"additional","affiliation":[{"name":"Ramon Castroviejo Institute for Ophthalmic Research, Complutense University of Madrid","place":["Madrid, Spain"]},{"name":"Health Research Institute of the Hospital Cl\u00ednico San Carlos (IdISSC)","place":["Madrid, Spain"]},{"name":"Department of Immunology, Ophthalmology and ENT, Faculty of Optics and Optometry, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel A.","family":"S\u00e1nchez-Puebla","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Carlos III University of Madrid","place":["Legan\u00e9s, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Granados","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Carlos III University of Madrid","place":["Legan\u00e9s, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana I.","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Ramon Castroviejo Institute for Ophthalmic Research, Complutense University of Madrid","place":["Madrid, Spain"]},{"name":"Health Research Institute of the Hospital Cl\u00ednico San Carlos (IdISSC)","place":["Madrid, Spain"]},{"name":"Department of Immunology, Ophthalmology and ENT, Faculty of Optics and Optometry, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Llorens","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Carlos III University of Madrid","place":["Legan\u00e9s, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN","place":["Wako, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences, Institute of Brain Science, Nagoya City University","place":["Nagoya, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Nieto-Vaquero","sequence":"additional","affiliation":[{"name":"Neurovascular Pathophysiology, Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC)","place":["Madrid, Spain"]},{"name":"Hospital 12 de Octubre Research Institute (i+12)","place":["Madrid, Spain"]},{"name":"University Institute for Research in Neurochemistry, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda A.","family":"Moro","sequence":"additional","affiliation":[{"name":"Neurovascular Pathophysiology, Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC)","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valent\u00edn","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Carlos III University of Madrid","place":["Legan\u00e9s, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 M.","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Ramon Castroviejo Institute for Ophthalmic Research, Complutense University of Madrid","place":["Madrid, Spain"]},{"name":"Health Research Institute of the Hospital Cl\u00ednico San Carlos (IdISSC)","place":["Madrid, Spain"]},{"name":"Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"de Hoz","sequence":"additional","affiliation":[{"name":"Ramon Castroviejo Institute for Ophthalmic Research, Complutense University of Madrid","place":["Madrid, Spain"]},{"name":"Health Research Institute of the Hospital Cl\u00ednico San Carlos (IdISSC)","place":["Madrid, Spain"]},{"name":"Department of Immunology, Ophthalmology and ENT, Faculty of Optics and Optometry, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/alz.12006","article-title":"Developing retinal biomarkers for the earliest stages of Alzheimer\u2019s disease: what we know, what we don\u2019t, and how to move forward","volume":"16","author":"Alber","year":"2020","journal-title":"Alzheimers 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