{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:35:46Z","timestamp":1788258946224,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Cleavage of Amyloid precursor protein by \u03b2- and \u03b3-secretases lead to A\u03b2 formation. The widely accepted pathogenic model states that these mutations cause AD via an increase in A\u03b2 formation and accumulation of A\u03b2 in Amyloid plaques. APP mutations cause early onset familial forms of Alzheimer\u2019s disease (FAD) in humans. We generated <jats:italic>App<\/jats:italic>\u2212Swedish (<jats:italic>App<jats:sup>s<\/jats:sup><\/jats:italic>) knock\u2212in rats, which carry a pathogenic <jats:italic>APP<\/jats:italic> mutation in the endogenous rat <jats:italic>App<\/jats:italic> gene. This mutation increases \u03b2-secretase processing of APP leading to both augmented A\u03b2 production and facilitation of glutamate release in <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> rats, via a \u03b2-secretase and APP\u2212dependent glutamate release mechanism. Here, we studied 11 to 14-month-old male and female <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> rats. To determine whether the Swedish <jats:italic>App<\/jats:italic> mutation leads to behavioral deficits, <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> knock-in rats were subjected to behavioral analysis using the IntelliCage platform, an automated behavioral testing system. This system allows behavioral assessment in socially housed animals reflecting a more natural, less stress-inducing environment and eliminates experimenter error and bias while increasing precision of measurements. Surprisingly, a spatial discrimination and flexibility task that can reveal deficits in higher order brain function showed that <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> females, but not <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> male rats, performed significantly worse than same sex controls. Moreover, female control rats performed significantly better than control and <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> male rats. The Swedish mutation causes a significant increase in A\u03b2 production in 14-month-old animals of both sexes. Yet, male and female <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> rats showed no evidence of AD\u2212related amyloid pathology. Finally, <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> rats did not show signs of significant neuroinflammation. Given that the APP Swedish mutation causes alterations in glutamate release, we analyzed Long-term potentiation (LTP), a long-lasting form of synaptic plasticity that is a cellular basis for learning and memory. Strikingly, LTP was significantly increased in <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> control females compared to both <jats:italic>App<jats:sup>s\/s<\/jats:sup><\/jats:italic> sexes and control males. In conclusion, this study shows that behavioral performances are sex and <jats:italic>App<\/jats:italic>-genotype dependent. In addition, they are associated with LTP values and not A\u03b2 or AD-related pathology. These data, and the failures of anti-A\u03b2 therapies in humans, suggest that alternative pathways, such as those leading to LTP dysfunction, should be targeted for disease-modifying AD therapy.<\/jats:p>","DOI":"10.3389\/fnagi.2022.1040576","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T05:44:25Z","timestamp":1668145465000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Late-long-term potentiation magnitude, but not A\u03b2 levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Metin","family":"Yesiltepe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc D.","family":"Tambini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel","family":"Breuillaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone P.","family":"Zehntner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"D\u2019Adamio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0197-4580(00)00124-X","article-title":"Inflammation and Alzheimer\u2019s disease.","volume":"21","author":"Akiyama","year":"2000","journal-title":"Neurobiol. 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