{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:56:50Z","timestamp":1788670610920,"version":"build-2803163510"},"reference-count":92,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021720","name":"The Olav Thon Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100021720","id-type":"DOI","asserted-by":"crossref"}]},{"name":"K. G. Jebsen Foundation"},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Centre of Excellence","award":["#223262"],"award-info":[{"award-number":["#223262"]}]},{"name":"National Infrastructure","award":["#197467"],"award-info":[{"award-number":["#197467"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyper-phosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer\u2019s disease. A majority of layer II projection neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer\u2019s disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-\u03b2, which is mimicked in a rat model that replicates the spatio-temporal cascade of the disease. Two important findings in relation to this are that reelin-signalling downregulates tau phosphorylation, and that oligomeric amyloid-\u03b2 interferes with reelin-signalling. Taking advantage of this rat model, we used proximity ligation assay to assess whether reelin and intracellular amyloid-\u03b2 directly interact during early, pre-plaque stages in anteriolateral entorhinal cortex layer II reelin-expressing neurons. We next made a viral vector delivering micro-RNA against reelin, along with a control vector, and infected reelin-expressing anteriolateral entorhinal cortex layer II-neurons to test whether reelin levels affect levels of intracellular amyloid-\u03b2 and\/or amyloid precursor protein. We analysed 25.548 neurons from 24 animals, which results in three important findings. First, in reelin-expressing anteriolateral entorhinal cortex layer II-neurons, reelin and intracellular amyloid-\u03b2 engage in a direct protein\u2013protein interaction. Second, injecting micro-RNA against reelin lowers reelin levels in these neurons, amounting to an effect size of 1.3\u20134.5 (Bayesian estimation of Cohen\u2019s d effect size, 95% credible interval). This causes a concomitant reduction of intracellular amyloid-\u03b2 ranging across three levels of aggregation, including a reduction of A\u03b242 monomers\/dimers amounting to an effect size of 0.5\u20133.1, a reduction of A\u03b2 prefibrils amounting to an effect size of 1.1\u20133.5 and a reduction of protofibrils amounting to an effect size of 0.05\u20132.1. Analysing these data using Bayesian estimation of mutual information furthermore reveals that levels of amyloid-\u03b2 are dependent on levels of reelin. Third, the reduction of intracellular amyloid-\u03b2 occurs without any substantial associated changes in levels of amyloid precursor protein. We conclude that reelin and amyloid-\u03b2 directly interact at the intracellular level in the uniquely reelin-expressing projection neurons in anteriolateral entorhinal cortex layer II, where levels of amyloid-\u03b2 are dependent on levels of reelin. Since amyloid-\u03b2 is known to impair reelin-signalling causing upregulated phosphorylation of tau, our findings are likely relevant to the vulnerability for neurofibrillary tangle-formation of this entorhinal neuronal population.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad115","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T07:34:51Z","timestamp":1680766491000},"source":"Crossref","is-referenced-by-count":16,"title":["Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-\u03b2"],"prefix":"10.1093","volume":"5","author":[{"given":"Asgeir","family":"Kobro-Flatmoen","sequence":"first","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"},{"name":"KG. Jebsen Centre for Alzheimer\u2019s Disease, NTNU , 7489, Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Battistin","sequence":"additional","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeevkumar Raveendran","family":"Nair","sequence":"additional","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiana","family":"Bjorkli","sequence":"additional","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belma","family":"Skender","sequence":"additional","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cliff","family":"Kentros","sequence":"additional","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"},{"name":"Mohn Research Center for the Brain, NTNU , 7489, Trondheim , Norway"},{"name":"Institute of Neuroscience, University of Oregon , 97401, Eugene, OR , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Gouras","sequence":"additional","affiliation":[{"name":"Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University , 221 84 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0285-1637","authenticated-orcid":false,"given":"Menno P","family":"Witter","sequence":"additional","affiliation":[{"name":"Kavli Institute for Systems Neuroscience MTFS, NTNU Norwegian University of Science and Technology , Olav Kyrres Gate 9, 7489, Trondheim , Norway"},{"name":"KG. Jebsen Centre for Alzheimer\u2019s Disease, NTNU , 7489, Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"issue":"4","key":"2023042113491006500_fcad115-B1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack CR","year":"2018","journal-title":"Alzheimers Dement"},{"issue":"11","key":"2023042113491006500_fcad115-B2","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.1016\/j.celrep.2019.11.044","article-title":"Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer\u2019s disease","volume":"29","author":"Pickett","year":"2019","journal-title":"Cell 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