{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T05:30:50Z","timestamp":1792215050218,"version":"4.4.0"},"reference-count":145,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fonds de recherche du Qu\u00e9bec-Sant\u00e9"},{"name":"Fondation du CHU de Qu\u00e9be"},{"DOI":"10.13039\/501100000143","name":"Alzheimer Society of Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000143","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fonds d\u2019Enseignement et de la Recherche"},{"DOI":"10.13039\/100007867","name":"Laval University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007867","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Central response to insulin is suspected to be defective in Alzheimer\u2019s disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood\u2013brain barrier and whether alterations of this interaction could contribute to Alzheimer\u2019s disease pathophysiology both remain poorly defined.<\/jats:p>\n               <jats:p>Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSR\u03b1-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSR\u03b1-B were lower in the parietal cortex of subjects diagnosed with Alzheimer\u2019s disease, positively correlating with cognitive scores, leading to a shift towards a higher INSR\u03b1-A\/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer\u2019s disease brain. Vascular INSR\u03b1 was inversely correlated with amyloid-\u03b2 plaques and \u03b2-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood\u2013brain barrier remained very low (&amp;lt;0.03 \u00b5l\/g\u00b7s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSR\u03b2 that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer\u2019s disease neuropathology induces insulin resistance at the level of the blood\u2013brain barrier.<\/jats:p>\n               <jats:p>Overall, the present data in post-mortem Alzheimer\u2019s disease brains and an animal model of Alzheimer\u2019s disease indicate that defects in the insulin receptor localized at the blood\u2013brain barrier strongly contribute to brain insulin resistance in Alzheimer\u2019s disease, in association with \u03b2-amyloid pathology.<\/jats:p>","DOI":"10.1093\/brain\/awac309","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:08:48Z","timestamp":1666656528000},"page":"75-90","source":"Crossref","is-referenced-by-count":108,"title":["Cerebrovascular insulin receptors are defective in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"146","author":[{"given":"Manon","family":"Leclerc","sequence":"first","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 Laval , Qu\u00e9bec, QC G1V 0A6 , Canada"},{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"},{"name":"Institut sur la Nutrition et les Aliments Fonctionnels (INAF) , Qu\u00e9bec, QC G1V 0A6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Bourassa","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 Laval , Qu\u00e9bec, QC G1V 0A6 , Canada"},{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyntia","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"Caron","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 Laval , Qu\u00e9bec, QC G1V 0A6 , Canada"},{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Sug\u00e8re","sequence":"additional","affiliation":[{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Emond","sequence":"additional","affiliation":[{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-554X","authenticated-orcid":false,"given":"David A","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center , Chicago, IL 60612 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4203-0887","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Calon","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 Laval , Qu\u00e9bec, QC G1V 0A6 , Canada"},{"name":"Axe Neurosciences, Centre de Recherche du CHU de Qu\u00e9bec-Universit\u00e9 Laval , Quebec, QC G1V 4G2 , Canada"},{"name":"Institut sur la Nutrition et les Aliments Fonctionnels (INAF) , Qu\u00e9bec, QC G1V 0A6 , 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