SENS PubMed Publication Search
Striking reduction of amyloid plaque burden in an Alzheimer’s mouse model after chronic administration of carmustine.
Hayes CD, Dey D, Palavicini JP, Wang H, Patkar KA, Minond D, Nefzi A, Lakshmana MK
Abstract:
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 (Abeta) reducing compound. To quantify Abeta 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 Abeta 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 Abeta starting from 5 microM by 39% (P <0.05), 10 microM by 51% (P <0.01) and 20 microM 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 (sAPPalpha) levels were increased to 167% (P <0.01) at 0.5 microM, 186% (P <0.05) at 1 microM, 204% (P <0.01) at 5 microM and 152% (P <0.05) at 10 microM compared to untreated cells. We also tested the effects of 12 structural derivatives of BCNU on Abeta levels, but none of them were as potent as BCNU. BCNU treatment at 5 microM 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 Abeta generation independent of secretases which were not altered up to 40microM. Interestingly, levels of transforming growth factor beta (TGFbeta) were increased at 5 microM (43%, P <0.05), 10 microM (73%, P <0.01) and 20 microM (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 Abeta 40 by 75% and amyloid plaque burden by 81%. Conversely, the levels of sAPPalpha were increased by 45%.
CONCLUSIONS:
BCNU reduces Abeta 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-Abeta drug. See related commentary article here 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.
METHODS:
We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Abeta) reducing compound. To quantify Abeta 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 Abeta 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 Abeta starting from 5 microM by 39% (P <0.05), 10 microM by 51% (P <0.01) and 20 microM 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 (sAPPalpha) levels were increased to 167% (P <0.01) at 0.5 microM, 186% (P <0.05) at 1 microM, 204% (P <0.01) at 5 microM and 152% (P <0.05) at 10 microM compared to untreated cells. We also tested the effects of 12 structural derivatives of BCNU on Abeta levels, but none of them were as potent as BCNU. BCNU treatment at 5 microM 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 Abeta generation independent of secretases which were not altered up to 40microM. Interestingly, levels of transforming growth factor beta (TGFbeta) were increased at 5 microM (43%, P <0.05), 10 microM (73%, P <0.01) and 20 microM (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 Abeta 40 by 75% and amyloid plaque burden by 81%. Conversely, the levels of sAPPalpha were increased by 45%.
CONCLUSIONS:
BCNU reduces Abeta 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-Abeta drug. See related commentary article here http://www.biomedcentral.com/1741-7015/11/82.
PMID: 23531149
Free Full-Text: http://www.biomedcentral.com/1741-7015/11/81
