科研之友
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摘要
Background: 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. Methods: We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Ab) reducing compound. To quantify A beta 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 beta 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. Results: BCNU decreased normalized levels of A beta starting from 5 mu M by 39% (P < 0.05), 10 mu M by 51% (P < 0.01) and 20 mu M by 63% (P < 0.01) in CHO cells compared to a control group treated with butyl amine, a structural derivative of BCNU. Interestingly, soluble amyloid precursor protein alpha (sAPP alpha) levels were increased to 167% (P < 0.01) at 0.5 mu M, 186% (P < 0.05) at 1 mu M, 204% (P < 0.01) at 5 mu M and 152% (P < 0.05) at 10 mu M compared to untreated cells. We also tested the effects of 12 structural derivatives of BCNU on A beta levels, but none of them were as potent as BCNU. BCNU treatment at 5 mu M 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 beta generation independent of secretases which were not altered up to 40 mu M. Interestingly, levels of transforming growth factor beta (TGF beta) were increased at 5 mu M (43%, P < 0.05), 10 mu M (73%, P < 0.01) and 20 mu M (92%, P < 0.001). Most significantly, cell culture results were confirmed in vivo after chronic administration of BCNU at 0.5 mg/kg which led to the reduction of A beta 40 by 75% and amyloid plaque burden by 81%. Conversely, the levels of sAPP alpha were increased by 45%. Conclusions: BCNU reduces A beta 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 beta drug.
- 出版日期2013-3-26
