{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:27:46Z","timestamp":1760059666989,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T00:00:00Z","timestamp":1751068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alberta Livestock and Meat Agency Ltd. (ALMA)","award":["2010R068R"],"award-info":[{"award-number":["2010R068R"]}]},{"name":"Minister of Science under the \u201cRegional Initiative of Excellence\u201d Program","award":["2010R068R"],"award-info":[{"award-number":["2010R068R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrPSc); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrPRes, generated by incubating wild-type mouse PrPC with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB\/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB\/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrPRes, moPrPRes + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrPSc accumulation, reactive astrogliosis, and amyloid-\u03b2 plaque deposition. Recombinant moPrPRes induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrPSc by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-\u03b2 plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrPRes and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrPSc. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders.<\/jats:p>","DOI":"10.3390\/ijms26136245","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6245","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipopolysaccharide and Recombinant Prion Protein Induce Distinct Neurodegenerative Pathologies in FVB\/N Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Seyed Ali","family":"Goldansaz","sequence":"first","affiliation":[{"name":"Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada"},{"name":"Sustainable Livestock Systems Branch, Sustainable Agri-Food Sciences Division, Agri-Food & Biosciences Institute, Hillsborough BT26 6DR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagnachew","family":"Hailemariam","sequence":"additional","affiliation":[{"name":"Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elda","family":"Dervishi","sequence":"additional","affiliation":[{"name":"Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1051-7591","authenticated-orcid":false,"given":"Grzegorz","family":"Zwierzchowski","sequence":"additional","affiliation":[{"name":"Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada"},{"name":"Faculty of Biology and Biotechnology, University of Warmia and Mazury, 1a Oczapowskiego Str., 10-719 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-6328","authenticated-orcid":false,"given":"Roman","family":"W\u00f3jcik","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, University of Warmia and Mazury, 1a Oczapowskiego Str., 10-719 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3207-2434","authenticated-orcid":false,"given":"David S.","family":"Wishart","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"},{"name":"Department of Computing Science, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0957-9373","authenticated-orcid":false,"given":"Burim N.","family":"Ametaj","sequence":"additional","affiliation":[{"name":"Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1126\/science.6801762","article-title":"Novel proteinaceous infectious particles cause scrapie","volume":"216","author":"Prusiner","year":"1982","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.tibs.2010.11.001","article-title":"Prion hypothesis: The end of the controversy?","volume":"36","author":"Soto","year":"2011","journal-title":"Trends Biochem. 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