Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine.
Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine.
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DOI：
10.1186/1741-7015-11-81
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发表时间：
2013-03-26
期刊：
影响因子：
9.3
通讯作者：
Lakshmana MK
中科院分区：
文献类型：
--
作者：
Hayes CD;Dey D;Palavicini JP;Wang H;Patkar KA;Minond D;Nefzi A;Lakshmana MK
目前针对阿尔茨海默病 (AD) 的可用疗法并不能治疗 AD 的根本原因。多项研究在疗养院的轶事观察强烈表明癌症与阿尔茨海默病之间存在反比关系。因此，我们推断肿瘤药物可能对 AD 有效。我们筛选了 FDA 批准的所有肿瘤药物库，并确定双氯乙基亚硝基脲（BCNU 或卡莫司汀）是一种有效的淀粉样蛋白 β (Aβ) 还原化合物。为了量化 Aβ 水平，将稳定表达淀粉样前体蛋白 751WT (APP751WT) 的中国仓鼠卵巢 (CHO) 细胞（称为 7WD10 细胞）暴露于不同浓度的 BCNU 48 小时，并收集条件培养基。为了检测 Aβ，将条件培养基用 Ab9 抗体进行免疫沉淀并进行免疫印迹检测。通过硫黄素 S 染色对长期暴露于 BCNU 的 AD 小鼠模型脑中的淀粉样斑块进行定量。与用 BCNU 结构衍生物丁胺处理的对照组相比，在 CHO 细胞中，从 5 μM 开始，BCNU 使 Aβ 标准化水平降低了 39% (P < 0.05)、10 μM 51% (P < 0.01) 和 20 μM 63% (P < 0.01)。有趣的是，与未处理的细胞相比，0.5 μM 时可溶性淀粉样前体蛋白 α (sAPPα) 水平增加至 167% (P < 0.01)，1 μM 时增加至 186% (P < 0.05)，5 μM 时增加至 204% (P < 0.01)，10 μM 时增加至 152% (P < 0.05)。我们还测试了 BCNU 的 12 种结构衍生物对 Aβ 水平的影响，但没有一个像 BCNU 那样有效。 5 μM BCNU 处理导致未成熟 APP 在细胞表面积累，导致未成熟 APP 表面与总 APP 的比例增加 184%，但成熟 APP 没有变化。同样值得注意的是，BCNU 减少了 Aβ 的生成，而与分泌酶无关，分泌酶在 40 μM 以内也没有改变。有趣的是，转化生长因子β（TGFβ）的水平在5 μM（43%，P < 0.05）、10 μM（73%，P < 0.01）和20 μM（92%，P < 0.001）时增加。最重要的是，长期施用 0.5 mg/kg BCNU 后，细胞培养结果在体内得到了证实，导致 Aβ40 减少 75%，淀粉样斑块负荷减少 81%。相反，sAPPα 的水平增加了 45%。 BCNU 可能通过改变细胞内 APP 的运输和加工，以无毒浓度减少 Aβ 生成和斑块负担。总而言之，这些数据提供了明确的证据，证明 BCNU 是一种有效的保留分泌酶的抗 Aβ 药物。请参阅此处相关评论文章http://www.biomedcentral.com/1741-7015/11/82
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. We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Aβ) reducing compound. To quantify Aβ 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 Aβ 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. BCNU decreased normalized levels of Aβ starting from 5 μM by 39% (P < 0.05), 10 μM by 51% (P < 0.01) and 20 μM 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 α (sAPPα) levels were increased to 167% (P < 0.01) at 0.5 μM, 186% (P < 0.05) at 1 μM, 204% (P < 0.01) at 5 μM and 152% (P < 0.05) at 10 μM compared to untreated cells. We also tested the effects of 12 structural derivatives of BCNU on Aβ levels, but none of them were as potent as BCNU. BCNU treatment at 5 μM 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 Aβ generation independent of secretases which were not altered up to 40 μM. Interestingly, levels of transforming growth factor beta (TGFβ) were increased at 5 μM (43%, P < 0.05), 10 μM (73%, P < 0.01) and 20 μM (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 Aβ40 by 75% and amyloid plaque burden by 81%. Conversely, the levels of sAPPα were increased by 45%. BCNU reduces Aβ 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-Aβ drug. See related commentary article here http://www.biomedcentral.com/1741-7015/11/82
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Huttunen, Henri J.;Peach, Camilla;Kovacs, Dora M.
通讯作者：
Kovacs, Dora M.
DOI：
10.1016/s0079-6468(09)04804-8
发表时间：
2009-01-01
期刊：
PROGRESS IN MEDICINAL CHEMISTRY, VOL 48
影响因子：
--
作者：
Albert, Jeffrey S.
通讯作者：
Albert, Jeffrey S.
影响因子：
4.8
作者：
Lakshmana, Madepalli K.;Chung, John Y.;Kang, David E.
通讯作者：
Kang, David E.
DOI：
10.1016/0272-0590(84)90097-6
发表时间：
1984-01-01
期刊：
FUNDAMENTAL AND APPLIED TOXICOLOGY
影响因子：
--
作者：
KEHRER, JP;PARAIDATHATHU, T
通讯作者：
PARAIDATHATHU, T