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In the present study, we intended to characterize the impact of IGF1R deficiency in the brain, focusing on PI3K\/Akt and MAPK\/ERK1\/2 signaling pathways and mitochondria-related parameters. For this purpose, we used 13-week-old UBC-CreERT2; Igf1rfl\/fl male mice in which Igf1r was conditionally deleted. IGF1R deficiency caused a decrease in brain weight as well as the activation of the IR\/PI3K\/Akt and inhibition of the MAPK\/ERK1\/2\/CREB signaling pathways. Despite no alterations in the activity of caspases 3 and 9, a significant alteration in phosphorylated GSK3\u03b2 and an increase in phosphorylated Tau protein levels were observed. In addition, significant disturbances in mitochondrial dynamics and content and altered activity of the mitochondrial respiratory chain complexes were noticed. An increase in oxidative stress, characterized by decreased nuclear factor E2-related factor 2 (NRF2) protein levels and aconitase activity and increased H2O2 levels were also found in the brain of IGF1R-deficient mice. Overall, our observations confirm the complexity of IGF1R in mediating brain signaling responses and suggest that its deficiency negatively impacts brain cells homeostasis and survival by affecting mitochondria and redox homeostasis.<\/jats:p>","DOI":"10.3390\/biomedicines9020158","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T20:51:51Z","timestamp":1612817511000},"page":"158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9866-933X","authenticated-orcid":false,"given":"Susana","family":"Cardoso","sequence":"first","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004\u2013504 Coimbra, Portugal"},{"name":"IIIUC\u2014Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal"},{"name":"CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5905-2978","authenticated-orcid":false,"given":"Ic\u00edar","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Lung Cancer and Respiratory Diseases Unit (CIBIR), Fundaci\u00f3n Rioja Salud, 26006 Logro\u00f1o, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8915-5687","authenticated-orcid":false,"given":"Sergio","family":"Pi\u00f1eiro-Hermida","sequence":"additional","affiliation":[{"name":"Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8580-0952","authenticated-orcid":false,"given":"Jos\u00e9","family":"Pichel","sequence":"additional","affiliation":[{"name":"Lung Cancer and Respiratory Diseases Unit (CIBIR), Fundaci\u00f3n Rioja Salud, 26006 Logro\u00f1o, Spain"},{"name":"Biomedical Research Networking Center in Respiratory Diseases (CIBERES), ISCIII, 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5177-6747","authenticated-orcid":false,"given":"Paula","family":"Moreira","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, University of Coimbra, 3004\u2013504 Coimbra, Portugal"},{"name":"CIBB\u2014Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute of Physiology, Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3389\/fncel.2017.00014","article-title":"Insulin-Like Growth Factor 1: At the Crossroads of Brain Development and Aging","volume":"11","author":"Wrigley","year":"2017","journal-title":"Front. 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