{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:55:25Z","timestamp":1791320125943,"version":"4.3.1"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"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"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      As Alzheimer\u2019s Disease (AD) and related dementias (ADRD) prevalence is projected to double by 2050, the urgency for relevant models to study its pathology intensifies. Aging is the primary risk factor for AD development and influenced by a myriad of factors including neurotoxic glial activation and BBB degradation; however, historically AD models consist of transgenic mouse\n                      <jats:italic>in-vivo<\/jats:italic>\n                      and\n                      <jats:italic>in-vitro<\/jats:italic>\n                      methods. While this offers many strengths, it is limited in their ability to mimic aging induced AD pathology. Currently, canine cognitive dysfunction (CCD) syndrome is being investigated as it is a natural and spontaneous disease with similar pathologies to AD and other dementias. Our lab and many others have worked extensively to characterize CCD pathology. However, the role of microglial and astrocytic activation and the interplay between the blood-brain barrier (BBB) have not been investigated. This study aims to fill this gap in knowledge in CCD and in turn its relation to human AD. We hypothesize that CCD-afflicted canines will exhibit increased neurotoxic glial activation and BBB degradation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods\/Results<\/jats:title>\n                    <jats:p>We utilized immunohistochemistry (IHC), morphological analyses, and immunofluorescence to investigate CCD pathology comparing CCD negative and CCD positive dogs. In this study we see glial morphology consistent with those seen in neurotoxic glia in neurodegenerative disease, increased S100\u03b2\/C3 astrocyte activation, decreased claudin-5 expression, and region-dependent perivascular AQP4 expression modulation in dogs with CCD, compared to those without CCD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results further characterize glial and BBB roles in CCD pathogenesis and reinforces the strengths of modeling AD\/ADRD in aging dogs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fragi.2026.1829442","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:43:24Z","timestamp":1780379004000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased neurotoxic gliosis and blood-brain barrier dysregulation in canine cognitive dysfunction syndrome (CCD)"],"prefix":"10.3389","volume":"7","author":[{"given":"Sean W.","family":"Boland","sequence":"first","affiliation":[{"name":"Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Brain Research Center, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta N.","family":"Coyner","sequence":"additional","affiliation":[{"name":"Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney J.","family":"Risen","sequence":"additional","affiliation":[{"name":"Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Brain Research Center, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullatif","family":"Alsulami","sequence":"additional","affiliation":[{"name":"Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Brain Research Center, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"McGrath","sequence":"additional","affiliation":[{"name":"Brain Research Center, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Center for Healthy Aging, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Brain Research Center, Colorado State University","place":["Fort Collins, CO, United States"]},{"name":"Center for Healthy Aging, Colorado State University","place":["Fort Collins, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrn1824","article-title":"Astrocyte\u2013endothelial interactions at the blood\u2013brain barrier","volume":"7","author":"Abbott","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1186\/s12917-025-05027-w","article-title":"Plasma and cerebrospinal fluid biomarkers in aged dogs with cognitive decline","volume":"21","author":"Alsulami","year":"2025","journal-title":"BMC Vet. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"8489","DOI":"10.1038\/srep08489","article-title":"euroinflammation and A\u03b2 accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation","volume":"5","author":"Carret-Rebillat","year":"2015","journal-title":"Sci. Rep."},{"key":"B4","unstructured":"Neurofibrillary tangles but not senile plaques parallel duration and severiti of azheimer\u2019s disease\n          \n          \n            \n              Arriagada\n              P.V.\n            \n            \n              Growdon\n              J. H.\n            \n            \n              Tessa Hedley-Whyte\n              E.\n            \n            \n              Hyman\n              B. T.\n            \n          \n          \n          1992"},{"key":"B5","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.jns.2012.07.010","article-title":"The vascular factor in Alzheimer\u2019s disease: a study in golgi technique and electron microscopy","volume":"322","author":"Baloyannis","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1242\/jcs.144550","article-title":"Non-muscle mlck is required for \u00df-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1\u00df-mediated barrier dysfunction in brain endothelial cells","volume":"127","author":"Beard","year":"2014","journal-title":"J. Cell Sci."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1016\/S0306-4522(98)00058-X","article-title":"Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood\u2013brain barrier breakdown in vivo","volume":"86","author":"Bolton","year":"1998","journal-title":"Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1007\/s11357-022-00655-8","article-title":"Associations between physical activity and cognitive dysfunction in older companion dogs: results from the dog aging project","volume":"45","author":"Bray","year":"2023","journal-title":"Geroscience"},{"key":"B8","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41598-018-36731-3","article-title":"Claudin-3-deficient C57BL\/6J mice display intact brain barriers","volume":"9","author":"Castro Dias","year":"","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12987-019-0150-9","article-title":"Claudin-12 is not required for blood-brain barrier tight junction function","volume":"16","author":"Castro Dias","year":"","journal-title":"Fluids Barriers CNS"},{"key":"B10","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1742-2094-7-6","article-title":"Serum levels of S100B and NSE proteins in Alzheimer\u2019s disease patients","volume":"7","author":"Chaves","year":"2010","journal-title":"J. Neuroinflammation"},{"key":"B11","first-page":"96","article-title":"Microglia efferocytosis: an emerging mechanism for the resolution of neuroinflammation in Alzheimer\u2019s disease","volume-title":"J. Neuroinflammation.","author":"Chen","year":"2025"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1038\/s41593-022-01167-6","article-title":"A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes","volume":"25","author":"Colombo","year":"2022","journal-title":"Nat. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1242\/dev.185140","article-title":"Fgfbp1 promotes blood-brain barrier development by regulating collagen IV deposition and maintaining Wnt\/\u03b2-catenin signaling","volume":"147","author":"Cottarelli","year":"2020","journal-title":"Development"},{"key":"B14","first-page":"463","article-title":"S100 proteins in Alzheimer\u2019s disease","volume-title":"Front. Neurosci","author":"Crist\u00f3va\u00f5","year":"2019"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1038\/sj.jcbfm.9600155","article-title":"Pericapillary haem-rich deposits: evidence for microhaemorrhages in aging human cerebral cortex","volume":"25","author":"Cullen","year":"2005","journal-title":"J. Cereb. Blood Flow Metabolism"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e01476","DOI":"10.1128\/mBio.01476-14","article-title":"Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals","volume":"5","author":"Daniels","year":"2014","journal-title":"mBio"},{"key":"B17","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s40659-024-00532-y","article-title":"Dissecting reactive astrocyte responses: lineage tracing and morphology-based clustering","volume":"57","author":"Delgado-Garc\u00eda","year":"2024","journal-title":"Biol. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"eadc9020","DOI":"10.1126\/science.adc9020","article-title":"Molecular basis of astrocyte diversity and morphology across the CNS in health and disease","volume":"378","author":"Endo","year":"2022","journal-title":"Sci. (1979)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"235","DOI":"10.3389\/fncel.2017.00235","article-title":"Microglia morphological categorization in a rat model of neuroinflammation by hierarchical cluster and principal components analysis","volume":"11","author":"Fern\u00e1ndez-Arjona","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1937\u201349","DOI":"10.1113\/jphysiol.2007.146852","article-title":"Differential effects of hydrocortisone and TNF\u03b1 on tight junction proteins in an in vitro model of the human blood\u2013brain barrier","volume":"586","author":"F\u00f6rster","year":"2008","journal-title":"J. Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"15955","DOI":"10.1038\/s41598-021-95535-0","article-title":"Microglial morphology in Alzheimer\u2019s disease and after A\u03b2 immunotherapy","volume":"11","author":"Franco-Bocanegra","year":"2021","journal-title":"Sci. Rep."},{"key":"B22","volume-title":"Claudin-5: Gatekeeper of Neurological Function","author":"Greene","year":"2019"},{"key":"B23","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/jcbfm.2015.44","article-title":"Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer\u2019s disease","volume":"36","author":"Halliday","year":"2016","journal-title":"J. Cereb. Blood Flow Metabolism"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e1012582","DOI":"10.1371\/journal.ppat.1012582","article-title":"Microglia-specific NF-\u03baB signaling is a critical regulator of prion-induced glial inflammation and neuronal loss","volume":"21","author":"Hay","year":"2025","journal-title":"PLoS Pathog."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1128521","DOI":"10.3389\/fnagi.2023.1128521","article-title":"Activated gliosis, accumulation of amyloid \u03b2, and hyperphosphorylation of tau in aging canines with and without cognitive decline","volume":"15","author":"Hines","year":"2023","journal-title":"Front. Aging Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/jcbfm.2013.76","article-title":"The APOE \u03b54\/\u03b54 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer\u2019s disease patients","volume":"33","author":"Hultman","year":"2013","journal-title":"J. Cereb. Blood Flow Metabolism"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.1007\/s00401-009-0486-3","volume-title":"Mechanisms of tau-induced Neurodegeneration","author":"Iqbal","year":"2009"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2692","DOI":"10.1007\/s13311-021-01126-2","article-title":"Upregulation of AQP4 improves blood\u2013brain barrier integrity and perihematomal edema following intracerebral hemorrhage","volume":"18","author":"Jeon","year":"2021","journal-title":"Neurotherapeutics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1500472","DOI":"10.1126\/sciadv.1500472","article-title":"Autoregulated paracellular clearance of amyloid-\u03b2 across the blood-brain barrier","volume":"1","author":"Keaney","year":"2015","journal-title":"Sci. Adv."},{"key":"B87","doi-asserted-by":"publisher","first-page":"121593","DOI":"10.1016\/j.lfs.2023.121593","article-title":"Aquaporin 4 is differentially increased and dislocated in association with tau and amyloid-beta","volume":"321","author":"Kecheliev","year":"2023","journal-title":"Life Sci."},{"key":"B30","article-title":"Neuroinflammation induces neurodegeneration","volume-title":"J. Neurol. Neurosurg. Spine.","author":"Kempuraj","year":"2016"},{"key":"B32","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s40035-020-00221-2","article-title":"Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes","volume":"9","author":"Kwon","year":"2020","journal-title":"Biomed. Cent. Ltd."},{"key":"B33","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/j.nbd.2010.10.023","article-title":"Reactive astrocytes and Wnt\/\u03b2-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson\u2019s disease","volume":"41","author":"L\u2019Episcopo","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"105493","DOI":"10.1016\/j.nbd.2021.105493","article-title":"Amyloid beta acts synergistically as a pro-inflammatory cytokine","volume":"159","author":"LaRocca","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0307577","DOI":"10.1371\/journal.pone.0307577","article-title":"Immune cell infiltration and modulation of the blood-brain barrier in a Guinea pig model of tuberculosis: observations without evidence of bacterial dissemination to the brain","volume":"19","author":"Latham","year":"2024","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"701673","DOI":"10.3389\/fncel.2021.701673","article-title":"Classification of microglial morphological phenotypes using machine learning","volume":"15","author":"Leyh","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"B39","volume-title":"Microglial Activation and Chronic Neurodegeneration","author":"Lull","year":"2013"},{"key":"B40","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.applanim.2015.08.034","article-title":"Assessment of severity and progression of canine cognitive dysfunction syndrome using the CAnine DEmentia scale (CADES)","volume":"171","author":"Madari","year":"2015","journal-title":"Appl. Anim. Behav. Sci."},{"key":"B41","volume-title":"Increased S10013 Neurotrophic Activity in Alzheimer\u2019s Disease Temporal Lobe","author":"Marshak","year":"1991"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e70630","DOI":"10.1002\/alz.70630","article-title":"The companion dog as a translational model for Alzheimer\u2019s disease: development of a longitudinal research platform and post mortem protocols","volume":"21","author":"McGrath","year":"2025","journal-title":"Alzheimer\u2019s Dementia"},{"key":"B43","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1038\/labinvest.2015.70","article-title":"TGF\u03b21 exacerbates blood-brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5","volume":"95","author":"McMillin","year":"2015","journal-title":"Lab. Investig."},{"key":"B44","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1002\/jmri.21731","article-title":"MRI and histological analysis of beta-amyloid plaques in both human alzheimer\u2019s disease and APP\/PS1 transgenic mice","volume":"29","author":"Meadowcroft","year":"2009","journal-title":"J. Magnetic Reson. Imaging"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1572286","DOI":"10.3389\/fvets.2025.1572286","article-title":"Blood\u2013brain barrier permeability changes in dogs with suspected canine cognitive dysfunction using magnetic resonance imaging subtraction enhancement analysis","volume":"12","author":"Merbl","year":"2025","journal-title":"Front. Vet. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"101295","DOI":"10.1016\/j.xpro.2022.101295","article-title":"Isolation and culture of pure adult mouse microglia and astrocytes for in vitro characterization and analyses","volume":"3","author":"Milner","year":"2022","journal-title":"Star. Protoc."},{"key":"B47","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1177\/0271678X17690761","article-title":"Differing associations between A\u03b2 accumulation, hypoperfusion, blood\u2013brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer\u2019s disease","volume":"38","author":"Miners","year":"2018","journal-title":"J. Cereb. Blood Flow Metabolism"},{"key":"B48","first-page":"457","article-title":"The contribution of neuroinflammation to amyloid toxicity in Alzheimer\u2019s disease","volume-title":"J. Neurochem.","author":"Minter","year":"2016"},{"key":"B49","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1002\/glia.20924","article-title":"Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"58","author":"Mori","year":"2010","journal-title":"Glia"},{"key":"B50","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.bbadis.2015.12.016","article-title":"Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer\u2019s disease","volume":"1862","author":"Nelson","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1083\/jcb.200302070","article-title":"Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice","volume":"161","author":"Nitta","year":"2003","journal-title":"J. Cell Biol."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21041225","article-title":"The pattern of AQP4 expression in the ageing human brain and in cerebral amyloid angiopathy","volume":"21","author":"Owasil","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"e70746","DOI":"10.1002\/alz.70746","article-title":"Amyloid beta and tau are associated with the dual effect of neuroinflammation on neurodegeneration","volume":"21","author":"Povala","year":"2025","journal-title":"Alzheimer\u2019s Dementia"},{"key":"B54","doi-asserted-by":"publisher","first-page":"573155","DOI":"10.3389\/fvets.2020.573155","article-title":"Nitrosative stress in the frontal cortex from dogs with canine cognitive dysfunction","volume":"7","author":"Prpar Mihevc","year":"2020","journal-title":"Front. Vet. Sci."},{"key":"B55","first-page":"5961","article-title":"Collagen type IV as the link between arterial stiffness and dementia","volume":"15","author":"Rabkin","year":"2023","journal-title":"Am. J. Transl. Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/s41531-021-00175-w","article-title":"Astrocytic atrophy as a pathological feature of Parkinson\u2019s disease with LRRK2 mutation","volume":"7","author":"Ramos-Gonzalez","year":"2021","journal-title":"NPJ Park. Dis."},{"key":"B57","doi-asserted-by":"publisher","first-page":"C1513","DOI":"10.1152\/ajpcell.00371.2011","article-title":"Interleukin-1\u03b2-induced barrier dysfunction is signaled through PKC-\u03b8 in human brain microvascular endothelium","volume":"302","author":"Rigor","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B58","first-page":"61","article-title":"Occludin deficiency affects stable junction maturation and apical-basal polarity in developing epithelia","volume":"147","author":"Saitou","year":"2000","journal-title":"J. Cell Biol."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-510x(02)00288-5","article-title":"Effect of APOE genotype on microvascular basement membrane in Alzheimer\u2019s disease","author":"Salloway","year":"2002"},{"key":"B60","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.tvjl.2010.05.014","article-title":"The canine cognitive dysfunction rating scale (CCDR): a data-driven and ecologically relevant assessment tool","volume":"188","author":"Salvin","year":"2011","journal-title":"Veterinary Journal Lond. Engl. 1997"},{"key":"B61","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1111\/bpa.12004","article-title":"Deficiency in mural vascular cells coincides with blood-brain barrier disruption in alzheimer\u2019s disease","volume":"23","author":"Sengillo","year":"2013","journal-title":"Brain Pathol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"50","DOI":"10.3390\/biomedicines11010050","article-title":"Analysis of cerebral small vessel changes in AD model mice","volume":"11","author":"Shibly","year":"2023","journal-title":"Biomedicines"},{"key":"B63","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/j.celrep.2017.04.047","article-title":"Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y1 receptor downregulation","volume":"19","author":"Shinozaki","year":"2017","journal-title":"Cell Rep."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1685430","DOI":"10.3389\/fvets.2025.16854","article-title":"Current practices for diagnosis and management of canine Cognitive Dysfunction Syndrome in the United States","volume":"12","author":"Simon","year":"2025","journal-title":"Front. Vet. Sci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1016\/j.neurobiolaging.2008.05.015","article-title":"Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain","volume":"31","author":"Simpson","year":"2010","journal-title":"Neurobiol. Aging"},{"key":"B66","doi-asserted-by":"publisher","first-page":"2892","DOI":"10.1038\/s41598-023-29894-1","article-title":"The tight junction protein occludin modulates blood\u2013brain barrier integrity and neurological function after ischemic stroke in mice","volume":"13","author":"Sugiyama","year":"2023","journal-title":"Sci. Rep."},{"key":"B67","first-page":"1055","article-title":"Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer\u2019S Disease","volume-title":"J Cereb Blood Flow Metab.","author":"Sweeney","year":"2015"},{"key":"B68","doi-asserted-by":"publisher","first-page":"575","DOI":"10.3233\/JAD-210040","article-title":"Mild microglial responses in the cortex and perivascular macrophage infiltration in subcortical white matter in dogs with age-related dementia modelling prodromal alzheimer\u2019s disease","volume":"82","author":"Thomsen","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"B69","volume-title":"Tumour Necrosis factor-\u00e1 Causes an Increase in blood-brain Barrier Permeability During Sepsis","author":"Tsao","year":"2021"},{"key":"B70","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/1423-0127-20-78","article-title":"Amyloid \u03b2 peptide-mediated neurotoxicity is attenuated by the proliferating microglia more potently than by the quiescent phenotype","volume":"20","author":"Tsay","year":"2013","journal-title":"J. Biomed. Sci."},{"key":"B71","volume-title":"ELSEVIER BB Biochi \u223cMAND Et Biophysica Aeta S100\/3 Expression in Alzheimer\u2019s Disease: Relation to Neuropathology in Brain Regions","author":"Van Eldik","year":"1994"},{"key":"B72","doi-asserted-by":"publisher","first-page":"113911","DOI":"10.1016\/j.celrep.2024.113911","article-title":"Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage","volume":"43","author":"V\u00e1zquez-Li\u00e9banas","year":"2024","journal-title":"Cell Rep."},{"key":"B73","first-page":"997786","article-title":"Microglia morphophysiological diversity and its implications for the CNS","volume-title":"Front. Immunol.","author":"Vidal-Itriago","year":"2022"},{"key":"B74","doi-asserted-by":"publisher","first-page":"169","DOI":"10.3389\/fneur.2018.00169","article-title":"Amyloid-\u03b2 Plaques in clinical Alzheimer\u2019s disease brain incorporate stable isotope tracer in vivo and exhibit nanoscale heterogeneity","volume":"9","author":"Wildburger","year":"2018","journal-title":"Front. Neurol."},{"key":"B75","first-page":"161","article-title":"Amyloid angiopathy and blood\u2013brain barrier changes in Alzheimer\u2019s diseasea","author":"Wisniewski","year":"1997"},{"key":"B76","volume-title":"Dysfunction Revealed by single-nucleus and Spatial Transcriptomics","author":"Yang","year":"2017"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3791\/57648","article-title":"Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using imagej","volume":"2018","author":"Young","year":"2018","journal-title":"J. Vis. Exp."},{"key":"B38","doi-asserted-by":"publisher","first-page":"152","DOI":"10.4103\/bc.bc_29_20","article-title":"Occludin regulation of blood\u2013brain barrier and potential therapeutic target in ischemic stroke","volume":"6","author":"Yuan","year":"2020","journal-title":"Brain Circ."},{"key":"B78","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nm.3913","article-title":"Neutrophils promote Alzheimer\u2019s disease-like pathology and cognitive decline via LFA-1 integrin","volume":"21","author":"Zenaro","year":"2015","journal-title":"Nat. Med."},{"key":"B79","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1001\/jamaneurol.2016.4370","article-title":"Association of perivascular localization of aquaporin-4 with cognition and alzheimer disease in aging brains","volume":"74","author":"Zeppenfeld","year":"2017","journal-title":"JAMA Neurol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1002\/glia.21118","article-title":"S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway","volume":"59","author":"Zhang","year":"2011","journal-title":"Glia"},{"key":"B81","doi-asserted-by":"publisher","first-page":"e0218415","DOI":"10.1371\/journal.pone.0218415","article-title":"Increased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice","volume":"14","author":"Zhang","year":"2019","journal-title":"PLoS One"},{"key":"B82","doi-asserted-by":"publisher","first-page":"e13501","DOI":"10.1111\/acel.13501","article-title":"Monomeric C-reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype-dependent pattern: a risk factor for Alzheimer\u2019s disease?","volume":"20","author":"Zhang","year":"2021","journal-title":"Aging Cell"},{"key":"B83","volume-title":"Amyloid \u0392-based Therapy for Alzheimer\u2019s Disease: Challenges, Successes and Future","author":"Zhang","year":"2023"},{"key":"B84","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.neurobiolaging.2006.05.016","article-title":"Microvascular injury and blood-brain barrier leakage in Alzheimer\u2019s disease","volume":"28","author":"Zipser","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"B85","doi-asserted-by":"publisher","first-page":"723\u201338","DOI":"10.1038\/nrn3114","article-title":"Neurovascular pathways to neurodegeneration in Alzheimer\u2019s disease and other disorders","volume":"12","author":"Zlokovic","year":"2011","journal-title":"Nat. Rev. Neurosci."}],"container-title":["Frontiers in Aging"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fragi.2026.1829442\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:43:31Z","timestamp":1780379011000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fragi.2026.1829442\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":86,"alternative-id":["10.3389\/fragi.2026.1829442"],"URL":"https:\/\/doi.org\/10.3389\/fragi.2026.1829442","relation":{},"ISSN":["2673-6217"],"issn-type":[{"value":"2673-6217","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"1829442"}}