{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:19:56Z","timestamp":1792113596080,"version":"4.4.0"},"reference-count":53,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"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>It has been suggested that functional traits of the adult brain\u2014all of which are established early in life\u2014may affect the brain\u2019s susceptibility to Alzheimer\u2019s disease (AD). Results of our previous studies on senescence-accelerated OXYS rats, a model of sporadic AD, support this hypothesis. Here, to elucidate the molecular genetic nature of the aberrations revealed during brain maturation, we analyzed transcriptomes (RNA-seq data) of the prefrontal cortex (PFC) and hippocampus of OXYS rats and Wistar (control) rats in the period of brain maturation critical for OXYS rats (ages P3 and P10; P: postnatal day). We found more than 1000 differentially expressed genes in both brain structures; functional analysis indicated reduced efficiency of the formation of neuronal contacts, presumably explained mainly by deficits of mitochondrial functions. Next, we compared differentially expressed genes in the rat PFC and hippocampus from infancy to the progressive stage of AD-like pathology (five ages in total). Three genes (Thoc3, Exosc8, and Smpd4) showed overexpression in both brain regions of OXYS rats throughout the lifespan. Thus, reduced efficiency of the formation of neural networks in the brain of OXYS rats in infancy likely contributes to the development of their AD-like pathology.<\/jats:p>","DOI":"10.3390\/ijms24021462","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T01:32:26Z","timestamp":1673487146000},"page":"1462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Rat Brain Transcriptome: From Infancy to Aging and Sporadic Alzheimer\u2019s Disease-like Pathology"],"prefix":"10.3390","volume":"24","author":[{"given":"Natalia A.","family":"Stefanova","sequence":"first","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-8544","authenticated-orcid":false,"given":"Nataliya G.","family":"Kolosova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (ICG SB RAS), 10 Lavrentyeva Ave., Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/978-1-4939-2627-5_31","article-title":"Advanced Neuroimaging Methods Towards Characterization of Early Stages of Alzheimer\u2019s Disease","volume":"1303","author":"Sepulcre","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"572","DOI":"10.3389\/fnins.2018.00572","article-title":"The Role of Magnetoencephalography in the Early Stages of Alzheimer\u2019s Disease","volume":"12","author":"Serrano","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e148","DOI":"10.1038\/emm.2014.121","article-title":"Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease","volume":"47","author":"Musiek","year":"2015","journal-title":"Exp. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jnnp-2014-310095","article-title":"Risk factors for predicting progression from mild cognitive impairment to Alzheimer\u2019s disease: A systematic review and meta-analysis of cohort studies","volume":"87","author":"Li","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s10522-015-9618-4","article-title":"Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer\u2019s disease","volume":"17","author":"Grimm","year":"2016","journal-title":"Biogerontology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.bbadis.2013.09.010","article-title":"The Alzheimer\u2019s disease mitochondrial cascade hypothesis: Progress and perspectives","volume":"1842","author":"Swerdlow","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.bbr.2016.05.007","article-title":"Transcriptional signatures of brain aging and Alzheimer\u2019s disease: What are our rodent models telling us?","volume":"322","author":"Hargis","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3233\/JAD-161088","article-title":"Oxidative Stress, Synaptic Dysfunction, and Alzheimer\u2019s Disease","volume":"57","author":"Trushina","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","unstructured":"Barchitta, M., Maugeri, A., La Rosa, M.C., Magnano San Lio, R., Favara, G., Panella, M., Cianci, A., and Agodi, A. (2018). Single Nucleotide Polymorphisms in Vitamin D Receptor Gene Affect Birth Weight and the Risk of Preterm Birth: Results From the \u201cMamma & Bambino\u201d Cohort and A Meta-Analysis. Nutrients, 10.","DOI":"10.3390\/nu10091172"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13195-018-0422-7","article-title":"Vulnerability and resilience to Alzheimer\u2019s disease: Early life conditions modulate neuropathology and determine cognitive reserve","volume":"10","author":"Lesuis","year":"2018","journal-title":"Alzheimers Res. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"834661","DOI":"10.3389\/fcell.2022.834661","article-title":"Early-Life Environment Influence on Late-Onset Alzheimer\u2019s Disease","volume":"10","author":"Gauvrit","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.siny.2018.10.003","article-title":"Late preterm births: New insights from neonatal neuroimaging and neurobehaviour","volume":"24","author":"Cheong","year":"2019","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e181726","DOI":"10.1001\/jamanetworkopen.2018.1726","article-title":"Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders","volume":"1","author":"Huang","year":"2018","journal-title":"JAMA Netw. Open"},{"key":"ref_18","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_19","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_20","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_21","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.exger.2018.11.008","article-title":"Alterations of hippocampal neurogenesis during development of Alzheimer\u2019s disease-like pathology in OXYS rats","volume":"115","author":"Rudnitskaya","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_22","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_23","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_24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s12864-018-4480-9","article-title":"Association of cerebrovascular dysfunction with the development of Alzheimer\u2019s disease-like pathology in OXYS rats","volume":"19","author":"Stefanova","year":"2018","journal-title":"BMC Genom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3984906","DOI":"10.1155\/2019\/3984906","article-title":"Suppression of Alzheimer\u2019s Disease-Like Pathology Progression by Mitochondria-Targeted Antioxidant SkQ1: A Transcriptome Profiling Study","volume":"2019","author":"Stefanova","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1093\/gerona\/gly198","article-title":"The Rat Prefrontal-Cortex Transcriptome: Effects of Aging and Sporadic Alzheimer\u2019s Disease-Like Pathology","volume":"74","author":"Stefanova","year":"2019","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Dib, S., Pahnke, J., and Gosselet, F. (2021). Role of ABCA7 in Human Health and in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094603"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/nrn.2017.29","article-title":"Not just amyloid: Physiological functions of the amyloid precursor protein family","volume":"18","author":"Deller","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"522","DOI":"10.2174\/1389202919666171229145156","article-title":"Early Life Stress and Epigenetics in Late-onset Alzheimer\u2019s Dementia: A Systematic Review","volume":"19","author":"Lemche","year":"2018","journal-title":"Curr. Genom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbi.2016.07.003","article-title":"Inflammation in Alzheimer\u2019s disease: Lessons learned from microglia-depletion models","volume":"61","author":"Spangenberg","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1089\/ars.2010.3815","article-title":"Transcriptional profile of genes involved in oxidative stress and antioxidant defense in a dietary murine model of steatohepatitis","volume":"15","author":"Gornicka","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.freeradbiomed.2017.12.016","article-title":"Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer\u2019s disease brain: A meta-analysis in human pathological specimens","volume":"115","author":"Zabel","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3389\/fneur.2020.00437","article-title":"Exploring Sphingolipid Implications in Neurodegeneration","volume":"11","author":"Alessenko","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1042\/BCJ20160010","article-title":"The role of TREX in gene expression and disease","volume":"473","author":"Heath","year":"2016","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1261\/rna.064626.117","article-title":"The RNA exosome and RNA exosome-linked disease","volume":"24","author":"Morton","year":"2018","journal-title":"RNA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15629","DOI":"10.1038\/s41598-020-72024-4","article-title":"Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer\u2019s disease, aging and other neuropsychiatric processes","volume":"10","author":"Karunakaran","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kozlova, T., Rudnitskaya, E., Burnyasheva, A., Stefanova, N., Peunov, D., and Kolosova, N. (2022). Delayed Formation of Neonatal Reflexes and of Locomotor Skills Is Associated with Poor Maternal Behavior in OXYS Rats Prone to Alzheimer\u2019s Disease-like Pathology. Biomedicines, 10.","DOI":"10.3390\/biomedicines10112910"},{"key":"ref_38","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_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/NPM-210803","article-title":"Commentary\u2014The late preterm infant: Vulnerable cerebral cortex and large burden of disability","volume":"15","author":"Volpe","year":"2022","journal-title":"J. Neonatal Perinat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sehar, U., Rawat, P., Reddy, A.P., Kopel, J., and Reddy, P.H. (2022). Amyloid Beta in Aging and Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112924"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rudnitskaya, E.A., Burnyasheva, A.O., Kozlova, T.A., Peunov, D.A., Kolosova, N.G., and Stefanova, N.A. (2022). Changes in Glial Support of the Hippocampus during the Development of an Alzheimer\u2019s Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031134"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/jpi.12248","article-title":"Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer\u2019s disease-like pathology","volume":"59","author":"Stefanova","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/alz.12220","article-title":"ABCA7 and the altered lipidostasis hypothesis of Alzheimer\u2019s disease","volume":"17","author":"Lyssenko","year":"2021","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_45","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_46","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.apsb.2021.06.014","article-title":"Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer\u2019s disease","volume":"12","author":"Austad","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/bs.pmbts.2016.12.017","article-title":"Mitochondria, Cybrids, Aging, and Alzheimer\u2019s Disease","volume":"146","author":"Swerdlow","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/geno.1994.1525","article-title":"Marked changes in mitochondrial DNA deletion levels in Alzheimer brains","volume":"23","author":"Horton","year":"1994","journal-title":"Genomics"},{"key":"ref_49","first-page":"596","article-title":"Influence of Antioxidant SkQ1 on Accumulation of Mitochondrial DNA Deletions in the Hippocampus of Senescence-Accelerated OXYS Rats","volume":"80","author":"Loshchenova","year":"2015","journal-title":"Biochemistry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.18632\/aging.102893","article-title":"Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer\u2019s disease","volume":"12","author":"Koh","year":"2020","journal-title":"Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1134\/S2079057022020114","article-title":"Astragalus membranaceus Increases Leukocyte Telomere Length, but Does Not Suppress Development of Accelerated Senescence Signs in OXYS Rats","volume":"12","author":"Kozhevnikova","year":"2022","journal-title":"Adv. Gerontol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.ajhg.2019.08.006","article-title":"Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis","volume":"105","author":"Magini","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nature13580","article-title":"Noncoding RNA transcription targets AID to divergently transcribed loci in B cells","volume":"514","author":"Pefanis","year":"2014","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1462\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:31Z","timestamp":1760119411000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":53,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021462"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021462","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}