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Considering the clear link between chronic A\u03b2 elevation and AD as well as tau pathology, the role(s) of A\u03b2 in TBI is of high importance. Endopeptidases, including the neprilysin (NEP)-like enzymes, are key mediators of A\u03b2 clearance and may affect susceptibility to pathology post-TBI. Here, we use a \u201chumanized\u201d mouse model of A\u03b2 production, which expresses normal human amyloid-beta precursor protein (APP) under its natural transcriptional regulation and exposed them to a more clinically relevant repeated closed-head TBI paradigm. These transgenic mice also were crossed with mice deficient for the A\u03b2 degrading enzymes NEP or NEP2 to assess models of reduced cerebral A\u03b2 clearance in our TBI model. Our results show that the presence of the human form of A\u03b2 did not exacerbate motor (Rotarod) and spatial learning\/memory deficits (Morris water maze) post-injuries, while potentially reduced anxiety (Open Field) was observed. NEP and NEP2 deficiency also did not exacerbate these deficits post-injuries and was associated with protection from motor (NEP and NEP2) and spatial learning\/memory deficits (NEP only). These data suggest that normally regulated expression of wild-type human APP\/A\u03b2 does not contribute to deficits acutely after TBI and may be protective at this stage of injury.<\/jats:p>","DOI":"10.1089\/neu.2020.6989","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T01:35:29Z","timestamp":1605144929000},"page":"665-676","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":8,"title":["Assessment of the Effects of Altered Amyloid-Beta Clearance on Behavior following Repeat Closed-Head Brain Injury in Amyloid-Beta Precursor Protein Humanized Mice"],"prefix":"10.1177","volume":"38","author":[{"given":"Kathleen C.","family":"Maigler","sequence":"first","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trevor J.","family":"Buhr","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher S.","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorothy A.","family":"Kozlowski","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Neuroscience Program, DePaul University, Chicago, Illinois, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Marr","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"e_1_3_4_2_2","unstructured":"Centers for Disease Control and Prevention. (2014). Surveillance Report of Traumatic Brain Injury-related Emergency Department Visits Hospitalizations and Deaths\u2014United States. www.cdc.gov\/traumaticbraininjury\/pdf\/TBI-Surveillance-Report-FINAL_508.pdf (Last accessed November23 2020)."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3171\/2013.7.JNS121822"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3171\/2012.10.FOCUS12284"},{"key":"e_1_3_4_5_2","first-page":"186","article-title":"Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment?","volume":"3","author":"Turner R.C.","year":"2012","unstructured":"Turner R.C., , Lucke-Wold B.P., , Robson M.J., , Omalu B.I., , Petraglia A.L., , and Bailes J.E. (2012). Repetitive traumatic brain injury and development of chronic traumatic encephalopathy: a potential role for biomarkers in diagnosis, prognosis, and treatment?. Front. 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