{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:53:22Z","timestamp":1788994402162,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T00:00:00Z","timestamp":1698364800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-15-00044"],"award-info":[{"award-number":["19-15-00044"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is an old-age neurodegenerative disorder; however, AD predisposition may arise early in life. Vascular dysfunction makes a big contribution to AD development. Nonetheless, the possible role of early-life vascular dysfunction in AD development is still poorly investigated. Here, using OXYS rats as a suitable model of the most common (sporadic) type of AD, we investigated maturation of the blood\u2013brain barrier (BBB) in the hippocampus and frontal cortex in the first 3 weeks of life. Using RNA-Seq data, we found an altered expression of BBB-associated genes in the middle of the first and second weeks of life in OXYS rats compared to control rats (Wistar strain). Moreover, by immunohistochemistry and electronic microscopy, we revealed a delay of vascularization and of subsequent pericyte coating of blood vessels in OXYS rats. These specific features were accompanied by an accelerated decrease in BBB permeability estimated using Evans blue dye. Notably, almost all of the observed differences from Wistar rats disappeared on postnatal day 20. Nonetheless, the observed features, which are characteristic of the postnatal period, may have long-term consequences and contribute to neurovascular dysfunction observed in OXYS rats late in life, thereby promoting early development of AD signs.<\/jats:p>","DOI":"10.3390\/ijms242115649","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T03:33:51Z","timestamp":1698377631000},"page":"15649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Postnatal Maturation of the Blood\u2013Brain Barrier in Senescence-Accelerated OXYS Rats, Which Are Prone to an Alzheimer\u2019s Disease-like Pathology"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3181-5934","authenticated-orcid":false,"given":"Ekaterina","family":"Rudnitskaya","sequence":"first","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Kozlova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Burnyasheva","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniil","family":"Peunov","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Tyumentsev","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Stefanova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-8544","authenticated-orcid":false,"given":"Nataliya","family":"Kolosova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.bcp.2013.12.018","article-title":"The role of amyloid-beta in the regulation of memory","volume":"88","author":"Morley","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15056","DOI":"10.1038\/nrdp.2015.56","article-title":"Alzheimer\u2019s Disease","volume":"1","author":"Masters","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.jalz.2019.04.001","article-title":"Duration of Preclinical, Prodromal, and Dementia Stages of Alzheimer\u2019s Disease in Relation to Age, Sex, and APOE Genotype","volume":"15","author":"Vermunt","year":"2019","journal-title":"Alzheimers Dement"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/01.wad.0000201854.62116.d7","article-title":"Early-Life Risk Factors for Alzheimer Disease","volume":"20","author":"Borenstein","year":"2006","journal-title":"Alzheimer Dis. Assoc. Disord"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40035-023-00355-z","article-title":"Early Life Adversity as a Risk Factor for Cognitive Impairment and Alzheimer\u2019s Disease","volume":"12","author":"Huang","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1159\/000439568","article-title":"Early Life Epidemiology of Alzheimer\u2019s Disease\u2014A Critical Review","volume":"45","author":"Seifan","year":"2015","journal-title":"Neuroepidemiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.neuroscience.2014.03.045","article-title":"Linking pathways in the developing and aging brain with neurodegeneration","volume":"269","author":"Kovacs","year":"2014","journal-title":"Neuroscience"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"825","DOI":"10.3389\/fnins.2018.00825","article-title":"Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration","volume":"12","author":"Nalivaeva","year":"2018","journal-title":"Front Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e818","DOI":"10.1542\/peds.2014-3556","article-title":"Late preterm birth and neurocognitive performance in late adulthood: A birth cohort study","volume":"135","author":"Heinonen","year":"2015","journal-title":"Pediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"898","DOI":"10.4161\/cc.28255","article-title":"Senescence-Accelerated OXYS Rats: A Model of Age-Related Cognitive Decline with Relevance to Abnormalities in Alzheimer Disease","volume":"13","author":"Stefanova","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.18632\/oncotarget.2751","article-title":"Amyloid Accumulation Is a Late Event in Sporadic Alzheimer\u2019s Disease-like Pathology in Nontransgenic Rats","volume":"6","author":"Stefanova","year":"2015","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.3233\/JAD-180065","article-title":"Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer\u2019s Disease-Like Pathology in OXYS Rats","volume":"63","author":"Tyumentsev","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rudnitskaya, E.A., Kozlova, T.A., Burnyasheva, A.O., Stefanova, N.A., and Kolosova, N.G. (2021). Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer\u2019s Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070823"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1126\/science.aat0473","article-title":"Glia as Architects of Central Nervous System Formation and Function","volume":"362","author":"Allen","year":"2018","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/BF00690476","article-title":"Electron microscopic studies on the fine structure of the blood vessels and perivascular spaces in the mammalian brain. A contribution to studies on the morphological principles of the so-called blood\u2013brain barrier","volume":"1","author":"Hager","year":"1961","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Daneman, R., Zhou, L., Agalliu, D., Cahoy, J.D., Kaushal, A., and Barres, B.A. (2010). The Mouse Blood-Brain Barrier Transcriptome: A New Resource for Understanding the Development and Function of Brain Endothelial Cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013741"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1152\/physrev.00050.2017","article-title":"Blood-Brain Barrier: From Physiology to Disease and Back","volume":"99","author":"Sweeney","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2011.08.039","article-title":"Basic and Therapeutic Aspects of Angiogenesis","volume":"146","author":"Potente","year":"2011","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2013.04.001","article-title":"Brain Development in Rodents and Humans: Identifying Benchmarks of Maturation and Vulnerability to Injury across Species","volume":"106\u2013107","author":"Semple","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41591-018-0297-y","article-title":"Blood\u2013Brain Barrier Breakdown Is an Early Biomarker of Human Cognitive Dysfunction","volume":"25","author":"Nation","year":"2019","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1148\/radiol.2017164043","article-title":"Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease","volume":"282","author":"Burgmans","year":"2017","journal-title":"Radiology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16","DOI":"10.2174\/187152709787601867","article-title":"Clearance of Amyloid-Beta Peptide across the Blood-Brain Barrier: Implication for Therapies in Alzheimer\u2019s Disease","volume":"8","author":"Deane","year":"2009","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.201412147","article-title":"Brain Barriers: Crosstalk between Complex Tight Junctions and Adherens Junctions","volume":"209","author":"Tietz","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/jcp.20647","article-title":"Possible Involvement of Gap Junctions in the Barrier Function of Tight Junctions of Brain and Lung Endothelial Cells","volume":"208","author":"Nagasawa","year":"2006","journal-title":"J. Cell Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1053\/j.semperi.2010.02.002","article-title":"Low Birth Weight Infants and the Developmental Programming of Hypertension: A Focus on Vascular Factors","volume":"34","author":"Ligi","year":"2010","journal-title":"Semin. Perinatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.matbio.2018.03.002","article-title":"Cervical Hyaluronan Biology in Pregnancy, Parturition and Preterm Birth","volume":"78\u201379","author":"Mahendroo","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1093\/eurheartj\/ehz025","article-title":"Mechanisms Linking Preterm Birth to Onset of Cardiovascular Disease Later in Adulthood","volume":"40","author":"Bavineni","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1093\/brain\/awt188","article-title":"Contribution of Cerebrovascular Disease in Autopsy Confirmed Neurodegenerative Disease Cases in the National Alzheimer\u2019s Coordinating Centre","volume":"136","author":"Toledo","year":"2013","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12987-021-00269-w","article-title":"Characterization of the blood\u2013brain barrier in genetically diverse laboratory mouse strains","volume":"18","author":"Schaffenrath","year":"2021","journal-title":"Fluids Barriers CNS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"533","DOI":"10.3389\/fnins.2020.00533","article-title":"Features of Postnatal Hippocampal Development in a Rat Model of Sporadic Alzheimer\u2019s Disease","volume":"14","author":"Rudnitskaya","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12987-019-0123-z","article-title":"Claudin-5: Gatekeeper of Neurological Function","volume":"16","author":"Greene","year":"2019","journal-title":"Fluids Barriers CNS"},{"key":"ref_32","unstructured":"Gao, H., and Gao, X. (2019). Brain Targeted Drug Delivery System, Academic Press."},{"key":"ref_33","first-page":"46","article-title":"Early-Life Hypoxia in the Development of Behavioral Dysfunctions in Accelerated-Senescence Oxys Rats, Correction with Antioxidants","volume":"20","author":"Korbolina","year":"2007","journal-title":"Adv. Gerontol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/S0165-0173(99)00024-7","article-title":"Brain Macrophages: On the Role of Pericytes and Perivascular Cells","volume":"31","author":"Thomas","year":"1999","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nrn1387","article-title":"Neurovascular Regulation in the Normal Brain and in Alzheimer\u2019s Disease","volume":"5","author":"Iadecola","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1177\/0271678X21992638","article-title":"Flow induces barrier and glycocalyx-related genes and negative surface charge in a lab-on-a-chip human blood\u2013brain barrier model","volume":"41","author":"Walter","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ana.410010502","article-title":"The Large Apparent Work Capability of the Blood-Brain Barrier: A Study of the Mitochondrial Content of Capillary Endothelial Cells in Brain and Other Tissues of the Rat","volume":"1","author":"Oldendorf","year":"1977","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.277.5323.242","article-title":"Pericyte Loss and Microaneurysm Formation in PDGF-B-Deficient Mice","volume":"277","author":"Lindahl","year":"1997","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.devcel.2011.07.001","article-title":"Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises","volume":"21","author":"Armulik","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nikolakopoulou, A.M., Zhao, Z., Montagne, A., and Zlokovic, B.V. (2017). Regional Early and Progressive Loss of Brain Pericytes but Not Vascular Smooth Muscle Cells in Adult Mice with Disrupted Platelet-Derived Growth Factor Receptor-\u03b2 Signaling. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176225"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/ng.2723","article-title":"Mutations in the Gene Encoding PDGF-B Cause Brain Calcifications in Humans and Mice","volume":"45","author":"Keller","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1038\/ncomms4413","article-title":"Astrocytic Laminin Regulates Pericyte Differentiation and Maintains Blood Brain Barrier Integrity","volume":"5","author":"Yao","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1056\/NEJMoa053727","article-title":"Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke","volume":"354","author":"Gould","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nn.3966","article-title":"GLUT1 Reductions Exacerbate Alzheimer\u2019s Disease Vasculo-Neuronal Dysfunction and Degeneration","volume":"18","author":"Winkler","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nature13241","article-title":"Mfsd2a Is a Transporter for the Essential Omega-3 Fatty Acid Docosahexaenoic Acid","volume":"509","author":"Nguyen","year":"2014","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nature13324","article-title":"Mfsd2a Is Critical for the Formation and Function of the Blood-Brain Barrier","volume":"509","author":"Lacoste","year":"2014","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1086\/380999","article-title":"A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene","volume":"74","author":"Dumitrescu","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrm2125","article-title":"Matrix Metalloproteinases and the Regulation of Tissue Remodelling","volume":"8","author":"Ewald","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1242\/dev.136507","article-title":"Reck Enables Cerebrovascular Development by Promoting Canonical Wnt Signaling","volume":"143","author":"Ulrich","year":"2016","journal-title":"Development"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Stefanova, N.A., Maksimova, K.Y., Rudnitskaya, E.A., Muraleva, N.A., and Kolosova, N.G. (2018). Association of Cerebrovascular Dysfunction with the Development of Alzheimer\u2019s Disease-like Pathology in OXYS Rats. BMC Genom., 19.","DOI":"10.1186\/s12864-018-4480-9"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Stefanova, N.A., and Kolosova, N.G. (2023). The Rat Brain Transcriptome: From Infancy to Aging and Sporadic Alzheimer\u2019s Disease-like Pathology. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021462"},{"key":"ref_52","unstructured":"Paxinos, G., and Watson, C. (2013). The Rat Brain in Stereotaxic Coordinates: Hard Cover Edition, Academic Press. [7th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15649\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:12:44Z","timestamp":1760130764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15649"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,27]]},"references-count":52,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115649"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115649","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,27]]}}}