{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:58:05Z","timestamp":1779170285771,"version":"3.51.4"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG073182"],"award-info":[{"award-number":["R01 AG073182"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG063407-03"],"award-info":[{"award-number":["R01AG063407-03"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["1RF1AG064821-01"],"award-info":[{"award-number":["1RF1AG064821-01"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Model organisms mimicking the pathogenesis of human diseases are useful for identifying pathogenic mechanisms and testing therapeutic efficacy of compounds targeting them. Models of Alzheimer\u2019s disease (AD) and related dementias (ADRD) aim to reproduce the brain pathology associated with these neurodegenerative disorders. Transgenic models, which involve random insertion of disease-causing genes under the control of artificial promoters, are efficient means of doing so. There are confounding factors associated with transgenic approaches, however, including target gene overexpression, dysregulation of endogenous gene expression at transgenes\u2019 integration sites, and limitations in mimicking loss-of-function mechanisms. Furthermore, the choice of species is important, and there are anatomical, physiological, and cognitive reasons for favoring the rat over the mouse, which has been the standard for models of neurodegeneration and dementia. We report an initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in (KI) Long-Evans rats with humanizing mutations in the A\u03b2-coding region of\n                    <jats:italic>App<\/jats:italic>\n                    , which encodes amyloid precursor protein (\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>h\/h<\/jats:sup>\n                    rats), using the IntelliCage, an automated operant social home cage system, at 6\u20138 weeks of age, then again at 4\u20135 months of age. These rats were previously generated as control organisms for studies on neurodegeneration involving other knock-in rat models from our lab.\n                    <jats:italic>App<\/jats:italic>\n                    <jats:sup>h\/h<\/jats:sup>\n                    rats of either sex can acquire place learning and reversal tasks. They can also acquire a diagonal sequencing task by 6\u20138 weeks of age, but not a more advanced serial reversal task involving alternating diagonals, even by 4\u20135 months of age. Thus, longitudinal behavioral analysis with the IntelliCage system can be useful to determine, in follow-up studies, whether KI rat models of Familial AD (FAD), sporadic late onset AD (LOAD), and of ADRD develop aging-dependent learning and memory deficits.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0263546","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T13:39:25Z","timestamp":1651671565000},"page":"e0263546","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in rats with humanizing mutations in the A\u03b2-coding region of App"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7518-3863","authenticated-orcid":true,"given":"Hoa","family":"Pham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0524-8075","authenticated-orcid":true,"given":"Tao","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2204-9441","authenticated-orcid":true,"given":"Luciano","family":"D\u2019Adamio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,5,4]]},"reference":[{"issue":"3","key":"pone.0263546.ref001","doi-asserted-by":"crossref","first-page":"e18006","DOI":"10.1371\/journal.pone.0018006","article-title":"The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function","volume":"6","author":"AP Barbagallo","year":"2011","journal-title":"PLoS One"},{"issue":"11","key":"pone.0263546.ref002","doi-asserted-by":"crossref","first-page":"8717","DOI":"10.1074\/jbc.C111.219873","article-title":"A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function","volume":"286","author":"AP Barbagallo","year":"2011","journal-title":"J Biol Chem"},{"issue":"11","key":"pone.0263546.ref003","doi-asserted-by":"crossref","first-page":"e15503","DOI":"10.1371\/journal.pone.0015503","article-title":"Tyr(682) in the intracellular domain of APP regulates amyloidogenic APP processing in vivo","volume":"5","author":"AP Barbagallo","year":"2010","journal-title":"PLoS One"},{"issue":"2\u20133","key":"pone.0263546.ref004","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00429-009-0221-9","article-title":"Modeling familial British and Danish dementia","volume":"214","author":"HJ Garringer","year":"2010","journal-title":"Brain Struct Funct"},{"issue":"11","key":"pone.0263546.ref005","doi-asserted-by":"crossref","first-page":"e7900","DOI":"10.1371\/journal.pone.0007900","article-title":"Generation and initial characterization of FDD knock in mice","volume":"4","author":"L Giliberto","year":"2009","journal-title":"PLoS One"},{"issue":"48","key":"pone.0263546.ref006","doi-asserted-by":"crossref","first-page":"20822","DOI":"10.1073\/pnas.1011689107","article-title":"Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits","volume":"107","author":"R Tamayev","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"44","key":"pone.0263546.ref007","doi-asserted-by":"crossref","first-page":"14915","DOI":"10.1523\/JNEUROSCI.3917-10.2010","article-title":"Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis","volume":"30","author":"R Tamayev","year":"2010","journal-title":"J Neurosci"},{"issue":"12","key":"pone.0263546.ref008","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1038\/emboj.2011.161","article-title":"APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant","volume":"30","author":"R Tamayev","year":"2011","journal-title":"EMBO J"},{"issue":"16","key":"pone.0263546.ref009","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1523\/JNEUROSCI.5193-11.2012","article-title":"\u2019Adamio L. 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