There have been several observations from multiple studies that suggest an inverse relationship between cancer and AD; cancer patients have been shown to have a lower risk of developing AD, and similarly, those diagnosed with AD seem to have a lower risk of developing cancer [11, 12]. Therefore, it seemed plausible that anticancer drugs may exert favorable effects on AD. By screening approximately 90 FDA-approved oncology drugs, a group led by Madepalli Lakshmana found that BCNU (1,3 bis(2-chloroethyl)-1-nitrosourea or carmustine), an alkylating agent currently used to treat patients with brain tumors, such as malignant gliomas, has potent activity in reducing Aβ production by cultured cells overexpressing APP [10]. Subsequent analysis of the mechanisms by which BCNU reduces Aβ production found that BCNU increases the secretion of APPα, a protein resulting from alternative α-cleavage of APP within the Aβ region, decreases the levels of C-terminal fragments of APP and increases the expression of immature APP on the cell surface. BCNU did not directly affect the enzymatic activities of β-, γ- and α-secretases. Accordingly, BCNU appears to reduce Aβ by altering the trafficking and processing of APP without directly affecting secretase activities. In addition, BCNU was found to increase transforming growth factor (TGF)-β1 levels in cell media and cell extracts, an intriguing observation in view of the involvement of the TGF-β1 pathway in AD [13].

Following these cell-based experiments, the authors performed in vivo experiments to determine whether BCNU could reduce Aβ production in a transgenic mouse model, in which Aβ plaques appear as early as six months of age. Intraperitoneal injection of 0.5 mg/kg BCNU, a non-toxic dose, for 60 days, from four to six months of age, resulted in the marked reduction of Aβ plaque burden in the brain. Furthermore, BCNU treatment decreased levels of Aβ and APP C-terminal fragments and increased levels of secreted APPα in mouse brains, recapitulating the changes observed in cell cultures. Moreover, BCNU treatment reduced the number of Iba1-positive microglia, indicating that this agent suppresses microglial activation in the mouse brain. This effect may be related to the TGF-β1 pathway, since TGF-β1 plays a constitutive role in the suppression of inflammation [14]. A modest increase in astroglial TGF-β1 production in APP transgenic mice has been shown to result in a significant reduction of Aβ [15]. Moreover, a specific impairment of the TGF-β1 signaling pathway has been demonstrated in the AD brain, and TGF-β1 has been found to exert neuroprotective effects against various insults, including Aβ toxicity [13, 14]. Thus, BCNU treatment may reduce Aβ production through combined effects on APP trafficking and processing and on the TGF-β1 pathway.