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

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

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

“…To minimize the variations in sample loading, we normalized the levels of A␤, CTFs, and sAPPs to that of actin. Ab9 antibody (N terminus mAb, epitope A␤1-16) was used to immunoprecipitate A␤, and a combination of 6E10/82E1 antibodies were used for detection (11,17,18). The result revealed a 3-fold increase (p Ͻ 0.001) in A␤ levels and more than a 3-fold increase (p Ͻ 0.001) in the CTF levels upon COPS5 overexpression (Fig.…”

Cancer and Dementia

“…Taxanes stabilize microtubules and have been proposed as potential therapeutic agents for AD and “related tauopathies.” 55 In animal studies, the APOE -directed cancer chemotherapy drug bexarotene was effective in clearing amyloid from the brains of mouse models of AD and also in improving their cognition; 56 the cancer drug carmustine with chronic administration also reduced beta amyloid generation and plaque burden in mice. 57 These findings have led to interest in repurposing oncology drugs for the treatment of AD. 58 Conversely, it has been proposed that if proteasome inhibitors are effective against cancer, then proteasome activators, including antioxidants, may be effective against neurodegeneration.…”

Potential repurposing of oncology drugs for the treatment of Alzheimer's disease

“…A paper by Hayes et al . published recently in BMC Medicine [10] describes an interesting oncology drug that may potentially be used as a disease-modifying drug in patients with AD.…”