Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine

BMC Medicine

Madepalli K Lakshmana³  Adel Nefzi²  Dimitriy Minond¹  Kshitij A Patkar²  Hongjie Wang³  Juan Pablo Palavicini³  Debleena Dey³  Crystal D Hayes³ 

[1] Peptide-based Therapeutics, Torrey Pines Institute for Molecular Studies, SW Village Parkway 11350, Port Saint Lucie, FL 34987, USA;Department of Chemistry, Torrey Pines Institute for Molecular Studies, SW Village Parkway 11350, Port Saint Lucie, FL 34987, USA;Section of Neurobiology, Torrey Pines Institute for Molecular Studies, SW Village Parkway 11350, Port Saint Lucie, FL 34987, USA

关键词: LDH release;    MTT assay;    cytotoxicity;    3 bis (2-chloroethyl)-1-nitrosourea;    1;    carmustine;    amyloid plaques;    amyloid-β;   

Others  :  857128
DOI  :  10.1186/1741-7015-11-81

 received in 2012-08-17, accepted in 2013-03-26,  发布年份 2013

【 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 (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.

Results

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%.

Conclusions

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 webcite

【 授权许可】

   
2013 Hayes et al; licensee BioMed Central Ltd.

【 图 表 】

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