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Recent studies indicate that at late stages of the amyloid pathology, LC\u2010pathological alterations accelerate AD\u2010like pathology progression by interfering with the neuromodulatory and anti\u2010inflammatory properties of NA. However, the impact of LC degeneration at the earliest stages of amyloidosis on the AD\u2010like pathology is not well understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The LC was lesioned in wild\u2010type and McGill\u2010R\u2010Thy1\u2010APP transgenic (APP tg) rats by administering<jats:italic>N<\/jats:italic>\u2010(2\u2010chloroethyl)\u2010<jats:italic>N<\/jats:italic>\u2010ethyl\u2010bromo\u2010benzylamine before amyloid plaque deposition. Cognitive deficits and AD\u2010like neuropathological changes were measured after the LC lesion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four months post\u2010treatment, rats displayed a decrease in brain noradrenergic innervation. The LC lesion in APP tg\u2010treated rats enhanced cognitive deficits and decreased hippocampal cholinergic innervation and neurotrophin expression. In addition, the APP tg\u2010treated rats displayed an increased microglial and astroglial cell number in close vicinity to hippocampal amyloid\u2010beta burdened neurons. The recruited microglia showed cellular alterations indicative of an intermediate activation state.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicate that early LC demise aggravates the early neuroinflammatory process, cognitive impairments, cholinergic deficits and neurotrophin deregulation at the earliest stages of the human\u2010like brain amyloidosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12835","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T09:40:18Z","timestamp":1657705218000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease"],"prefix":"10.1111","volume":"48","author":[{"given":"Lisi","family":"Flores\u2010Aguilar","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Orciani","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurosurgery McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan K.","family":"Foret","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Kovecses","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Ducatenzeiler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-7433","authenticated-orcid":false,"given":"A. 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