Multitarget strategy of traditional Chinese medicine in treatment of Alzheimer's disease

Abstract

critical brain regions is considered to be a causative factor in the cognitive decline and neuronal degeneration associated with Alzheimer’s disease (AD). Thus, reducing levels of toxic A b species by inhibiting BACE may be a viable therapeutic strategy for the treatment of AD. Effectively selecting BACE inhibitors for in vivo profiling requires high confidence in the translatability of in vitro potency. Human iPS-derived neurons, which more closely represent human neurons, have been proposed to be a superior cellular model for translating in vitro potency to in vivo (and later clinical) efficacy. Methods: BACE inhibitors representing 3 chemical series were chosen for profiling in a soluble enzyme assay, an APP over-expressing human H4 neuroglioma cell line, a rodent primary neuronal culture, and in human iPS-derived neurons. Our human iPS line was derived from adult non-diseased fibroblasts that were reprogrammed into GABAergic neurons. IC50 correlations for A b lowering were built to compare potency across these assays. Additionally, wild-type 129/SVEmicewere dosed with several of these BACE inhibitors to establish the in vivo brain IC50 for A b. For all assays, in vitro -toin vivo correlations (IVIVCs) of in vitro IC50 values and in vivo IC50 values were generated.Results:We report a high correlation in BACE inhibitor potency between all the in vitro assays examined, including the iPS-derived neurons. Additionally, IVIVCs for the various in vitro assays described translate well to in vivo rodent efficacy. Conclusions: Selecting appropriate chemical matter for in vivo profiling is essential for efficient drug discovery. While the non-diseased human iPS-derived neurons that we tested are more representative of human neurons than the other assay models examined, they do not provide any distinct advantage in translating in vitro potency to in vivo efficacy and thus do not appear to represent a superior translatable cellular model for screening. It remains to be seen if iPSderived neurons from AD patients offer any advantage in screening for Alzheimer’s disease therapeutics.