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Here, we demonstrate that protein variant pathology generated in brain tissue of an experimental TBI mouse model is similar to protein variant pathology observed during early stages of AD, and that subacute accumulation of AD associated variants of amyloid beta (A\u03b2) and tau in the TBI mouse model correlated with behavioral deficits. Male C57BL\/6 mice were subjected to midline fluid percussion injury or to sham injury, after which sensorimotor function (rotarod, neurological severity score), cognitive deficit (novel object recognition), and affective deficits (elevated plus maze, forced swim task) were assessed post-injury (DPI). Protein pathology at 7, 14, and 28 DPI was measured in multiple brain regions using an immunostain panel of reagents selectively targeting different neurodegenerative disease-related variants of A\u03b2, tau, TDP-43, and alpha-synuclein. Overall, TBI resulted in sensorimotor deficits and accumulation of AD-related protein variant pathology near the impact site, both of which returned to sham levels by 14 DPI. Individual mice, however, showed persistent behavioral deficits and\/or accumulation of toxic protein variants at 28 DPI. Behavioral outcomes of each mouse were correlated with levels of seven different protein variants in ten brain regions at specific DPI. Out of 21 significant correlations between protein variant levels and behavioral deficits, 18 were with variants of A\u03b2 or tau. Correlations at 28 DPI were all between a single A\u03b2 or tau variant, both of which are strongly associated with human AD cases. These data provide a direct mechanistic link between protein pathology resulting from TBI and the hallmarks of AD.<\/jats:p>","DOI":"10.1007\/s12035-024-04035-5","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T16:03:42Z","timestamp":1709049822000},"page":"7567-7582","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Traumatic Brain Injury in Mice Generates Early-Stage Alzheimer\u2019s Disease Related Protein Pathology that Correlates with Neurobehavioral Deficits"],"prefix":"10.1007","volume":"61","author":[{"given":"Nicholas","family":"Panayi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lifshitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel K.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Sierks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,27]]},"reference":[{"key":"4035_CR1","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1177\/0963689717714102","volume":"26","author":"M Galgano","year":"2017","unstructured":"Galgano M, Toshkezi G, Qiu X, Russell T, Chin L, Zhao LR (2017) Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors. 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