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Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer\u2019s-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated. Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (\u03b1-SMA).These changes coincided with increased aggregation of variable-length amyloid peptides including A\u03b2<jats:sub>1-40\/42,<\/jats:sub> A\u03b2<jats:sub>1-16,<\/jats:sub> and \u03b2-secretase-derived fragment (\u03b2CTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of A\u03b2<jats:sub>1-40\/42<\/jats:sub> peptides were also observed in the leptomeningeal arteries of young TBI patients. These pathological changes also included higher \u03b2-secretase (BACE1) when compared to \u03b1-secretase A Disintegrin And Metalloprotease 10 (ADAM10) expression in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased \u03b2CTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.<\/jats:p>","DOI":"10.1007\/s00401-025-02848-9","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T15:54:20Z","timestamp":1737561260000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Traumatic brain injury causes early aggregation of beta-amyloid peptides and NOTCH3 reduction in vascular smooth muscle cells of leptomeningeal arteries"],"prefix":"10.1007","volume":"149","author":[{"given":"Ilknur","family":"\u00d6zen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami Abu","family":"Hamdeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Ruscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Marklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"2848_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113257","volume":"328","author":"EE Abrahamson","year":"2020","unstructured":"Abrahamson EE, Ikonomovic MD (2020) Brain injury-induced dysfunction of the blood brain barrier as a risk for dementia. 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