{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:52:41Z","timestamp":1782280361001,"version":"3.54.5"},"posted":{"date-parts":[[2025,1,29]]},"group-title":"Molecular Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cerebrovascular inflammation is prevalent in a majority of Alzheimer\u2019s patients. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), circulating in the plasma have been shown to cause the inflammation of blood-brain barrier (BBB) endothelium lining the cerebral microvasculature. The BBB inflammation has been implicated in the increase of toxic A\u03b2 accumulation within Alzheimer\u2019s disease (AD) brain. TNF-alpha in the peripheral circulation can aggravate the accumulation of amyloid-beta (A\u03b2) peptides in Alzheimer\u2019s disease brain. In the current study, we have shown that the exposure to TNF-alpha leads to an increase in A\u03b242 accumulation in mice and BBB endothelial cells in vitro. Moreover, dynamic SPECT\/CT imaging in wild-type (WT) mice infused with TNF-alpha increased the permeability and influx of A\u03b242 into the mice brain. In addition, our results show that TNF-alpha modifies the expression of cofilin, actin, and dynamin, which are critical components for A\u03b2 endocytosis by BBB endothelial cells. These results offer a mechanistic understanding of how TNF-alpha may promote A\u03b2 accumulation at the BBB and the underlying interactions between inflammation and A\u03b2 exposure that drives BBB dysfunction. Hence, a therapeutic intervention aimed at addressing cerebrovascular inflammation in Alzheimer\u2019s disease may potentially reduce A\u03b2 induced cerebrovascular toxicity in Alzheimer\u2019s disease brain.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance statement<\/jats:title>\n                  <jats:p>\n                    Increased levels of TNF-alpha circulating in the plasma are considered significant factors in the consequences of A\u03b2 pathology in Alzheimer\u2019s disease, where it can promote cerebrovascular inflammation and BBB dysfunction. However, the role of TNF-alpha, in exacerbating A\u03b2 pathology by increasing A\u03b2 accumulation at the BBB endothelial cells remains only partially understood. In this study, we demonstrated that TNF-alpha enhances A\u03b242 accumulation in the BBB endothelium by altering the expression of the BBB endocytosis machinery, specifically cofilin, actin, and dynamin. These findings are anticipated to contribute to the development of therapeutic approaches aimed at addressing elevated cytokine levels in Alzheimer\u2019s disease.\n                    <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                      <jats:label>Graphical Abstract<\/jats:label>\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"635286v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                    <\/jats:fig>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.28.635286","type":"posted-content","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T22:30:17Z","timestamp":1738189817000},"source":"Crossref","is-referenced-by-count":2,"title":["Elucidating Molecular Mechanisms Governing TNF-Alpha-Mediated Regulation of Amyloid Beta 42 Uptake in Blood-Brain Barrier Endothelial 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