{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:04:54Z","timestamp":1782281094734,"version":"3.54.5"},"posted":{"date-parts":[[2025,11,10]]},"group-title":"Neuroscience","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"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":"crossref","award":["AG069502"],"award-info":[{"award-number":["AG069502"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["AG066511"],"award-info":[{"award-number":["AG066511"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["AG062581"],"award-info":[{"award-number":["AG062581"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["NS96050"],"award-info":[{"award-number":["NS96050"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>In murine models of Alzheimer\u2019s disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>TgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>DSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and\/or cognition individually, but few interactions were found and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>Combined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research-in-Context<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>Systemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimer\u2019s disease (AD)-like neuropathology and behavior in murine models of AD. However, the impact of LC degeneration in an animal model that expresses both amyloid and endogenous tau pathology at a time point before the emergence of significant forebrain pathology is underexplored.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Interpretation: We expanded the behavioral and molecular characterization of TgF344-AD rats in response to N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)-induced LC lesions during the pre-pathology stages of disease. Unexpectedly, we found that TgF344-AD genotype and DSP-4 rarely interacted to exacerbate AD-related symptoms or pathology.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Future Directions: Our results indicate LC lesions do not accelerate onset of AD-like neuropathology or behavioral impairment in this model. Future studies in older TgF344-AD animals and using different DSP-4 treatment regimens would help clarify the relationship between LC integrity and AD progression.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Locus coeruleus damage causes apathy-like behavior and changes in arousal<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>TgF344-AD genotype induces social recognition deficits and anxiety-like behavior<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Locus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficits<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Interactions that exacerbate Alzheimer\u2019s disease neuropathology were also scarce<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.09.687363","type":"posted-content","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T04:25:58Z","timestamp":1762835158000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of early locus coeruleus lesions in the TgF344 Alzheimer\u2019s disease rat model"],"prefix":"10.64898","author":[{"given":"Alexia E.","family":"Marriott","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Schroeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anu","family":"Korukonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany S.","family":"Pate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine E.","family":"McCann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Weinshenker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Kelberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111206000955000_2025.11.09.687363v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2018.01.010"},{"key":"2025111206000955000_2025.11.09.687363v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318232a379"},{"key":"2025111206000955000_2025.11.09.687363v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410320510"},{"key":"2025111206000955000_2025.11.09.687363v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-022-02477-6"},{"key":"2025111206000955000_2025.11.09.687363v1.5","first-page":"1","article-title":"Locus coeruleus cellular and molecular pathology during the progression of Alzheimer\u2019s disease","volume":"5","year":"2017","journal-title":"Acta Neuropathol Commun"},{"key":"2025111206000955000_2025.11.09.687363v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.06.2362"},{"key":"2025111206000955000_2025.11.09.687363v1.7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3233\/JAD-180688","article-title":"Neuropathologic correlates of psychiatric symptoms in Alzheimer\u2019s disease","volume":"66","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2025111206000955000_2025.11.09.687363v1.8","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.3233\/JAD-215546","article-title":"Consequences of hyperphosphorylated tau in the locus coeruleus on behavior and cognition in a rat model of Alzheimer\u2019s disease","volume":"86","year":"2022","journal-title":"J Alzheimer\u2019s Dis"},{"key":"2025111206000955000_2025.11.09.687363v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2023.01.016"},{"key":"2025111206000955000_2025.11.09.687363v1.10","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx232"},{"key":"2025111206000955000_2025.11.09.687363v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41386-022-01293-6"},{"key":"2025111206000955000_2025.11.09.687363v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14131"},{"key":"2025111206000955000_2025.11.09.687363v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abj2511"},{"key":"2025111206000955000_2025.11.09.687363v1.14","doi-asserted-by":"publisher","DOI":"10.1097\/00002093-198701040-00005"},{"key":"2025111206000955000_2025.11.09.687363v1.15","doi-asserted-by":"crossref","unstructured":"Flores-Aguilar L, Hall H, Orciani C, Foret MK, Kovecses O, Ducatenzeiler A, et al. 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