Abstract
BackgroundCurrently 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.MethodsWe 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.ResultsBCNU 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%.ConclusionsBCNU 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
Highlights
Available therapies for Alzheimer’s disease (AD) do not treat the underlying cause of AD
We screened a library of all the Food and Drug Administration (FDA)-approved oncology drugs totaling 89 compounds obtained from NCI/NIH [27] at a concentration of 10.0 μM to determine their effects on amyloid b peptide (Ab) levels by immunoprecipitation of Ab in the conditioned medium (CM) and Western blotting
To test the effect of different concentrations of bis (2chloroethyl)-1-nitrosourea (BCNU), Chinese hamster ovary (CHO) cells stably expressing APP751WT (7WD10) were treated for 48 hours and the CM were immunoprecipitated with Ab9 antibody which recognizes an epitope within 1-16 amino acids of Ab peptide
Summary
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. With the failure of anti-amyloid therapy to improve cognitive measures in clinical trials including the most recent (semagacestat [5,6], homotaurine [7] tarenfurbil [8] and bapineuzumab [9]), the so called amyloid ‘naysayers’ are vocally suggesting that anti-amyloid therapeutic approaches be abandoned. Improved cognitive measures that correlate well with decreased Ab levels, even up to 4.5 years after the initial vaccination with Ab in clinical trials [10,11], strongly support Ab’s causal role in AD and clearly suggest that reducing Ab levels in the brains of AD patients is an effective approach for successful therapy. Accelerated cortical atrophy continues to be well correlated with high Ab deposition in multiple studies which used the most advanced technology and tracing compounds, further strengthening the pivotal role of Ab in AD [12,13]
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