{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T07:30:56Z","timestamp":1769499056956,"version":"3.49.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2013,3,26]],"date-time":"2013-03-26T00:00:00Z","timestamp":1364256000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Currently available therapies for Alzheimer's disease (AD) do not treat the underlying cause of AD. Anecdotal observations in nursing homes from multiple studies strongly suggest an inverse relationship between cancer and AD. Therefore, we reasoned that oncology drugs may be effective against AD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (A\u03b2) reducing compound. To quantify A\u03b2 levels, Chinese hamster ovary (CHO) cells stably expressing amyloid precursor protein 751WT (APP751WT) called 7WD10 cells were exposed to different concentrations of BCNU for 48 hours and the conditioned media were collected. To detect A\u03b2 the conditioned media were immunoprecipitated with Ab9 antibody and subjected to immunoblot detection. Amyloid plaques were quantified in the brains of a mouse model of AD after chronic exposure to BCNU by thoflavin S staining.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>BCNU decreased normalized levels of A\u03b2 starting from 5 \u03bcM by 39% (<jats:italic>P<\/jats:italic> &lt; 0.05), 10 \u03bcM by 51% (<jats:italic>P<\/jats:italic> &lt; 0.01) and 20 \u03bcM by 63% (<jats:italic>P<\/jats:italic> &lt; 0.01) in CHO cells compared to a control group treated with butyl amine, a structural derivative of BCNU. Interestingly, soluble amyloid precursor protein \u03b1 (sAPP\u03b1) levels were increased to 167% (<jats:italic>P<\/jats:italic> &lt; 0.01) at 0.5 \u03bcM, 186% (<jats:italic>P<\/jats:italic> &lt; 0.05) at 1 \u03bcM, 204% (<jats:italic>P<\/jats:italic> &lt; 0.01) at 5 \u03bcM and 152% (<jats:italic>P<\/jats:italic> &lt; 0.05) at 10 \u03bcM compared to untreated cells. We also tested the effects of 12 structural derivatives of BCNU on A\u03b2 levels, but none of them were as potent as BCNU. BCNU treatment at 5 \u03bcM led to an accumulation of immature APP at the cell surface resulting in an increased ratio of surface to total APP by 184% for immature APP, but no change in mature APP. It is also remarkable that BCNU reduced A\u03b2 generation independent of secretases which were not altered up to 40 \u03bcM. Interestingly, levels of transforming growth factor beta (TGF\u03b2) were increased at 5 \u03bcM (43%, <jats:italic>P<\/jats:italic> &lt; 0.05), 10 \u03bcM (73%, <jats:italic>P<\/jats:italic> &lt; 0.01) and 20 \u03bcM (92%, <jats:italic>P<\/jats:italic> &lt; 0.001). Most significantly, cell culture results were confirmed <jats:italic>in vivo<\/jats:italic> after chronic administration of BCNU at 0.5 mg\/kg which led to the reduction of A\u03b240 by 75% and amyloid plaque burden by 81%. Conversely, the levels of sAPP\u03b1 were increased by 45%.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>BCNU reduces A\u03b2 generation and plaque burden at non-toxic concentrations possibly through altered intracellular trafficking and processing of APP. Taken together these data provided unequivocal evidence that BCNU is a potent secretase-sparing anti-A\u03b2 drug.<\/jats:p>\n            <jats:p>See related commentary article here <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.biomedcentral.com\/1741-7015\/11\/82\" ext-link-type=\"uri\">http:\/\/www.biomedcentral.com\/1741-7015\/11\/82<\/jats:ext-link>\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1741-7015-11-81","type":"journal-article","created":{"date-parts":[[2013,3,26]],"date-time":"2013-03-26T09:14:21Z","timestamp":1364289261000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine"],"prefix":"10.1186","volume":"11","author":[{"given":"Crystal D","family":"Hayes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debleena","family":"Dey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Pablo","family":"Palavicini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kshitij A","family":"Patkar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitriy","family":"Minond","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adel","family":"Nefzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madepalli K","family":"Lakshmana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,3,26]]},"reference":[{"key":"765_CR1","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.jalz.2010.01.010","volume":"6","author":"A Wimo","year":"2010","unstructured":"Wimo A, Winblad B, Johnson L: The worldwide societal costs of dementia: estimates for 2009. 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