A? oligomer concentration in mouse and human brain and its drug-induced reduction ex vivo

The elimination of amyloid beta (AO) oligomers is a promising strategy for therapeutic drug development of Alzheimer's disease (AD). AD mouse models that develop AD pathology have been used to demonstrate in vivo efficacy of compounds that later failed in clinical development. Here, we analyze the concentration and size distribution of AD oligomers in different transgenic mouse models of AD and in human brain samples by surface-based fluorescence intensity distribution analysis (sFIDA), a highly sensitive method for detecting and quantitating protein aggregates. We demonstrate dose-and time-dependent oligomer elimination by the compound RD2 in mouse and human AD brain homogenates as sources of native AD oligomers. Such ex vivo target engagement analyses with mouse-and human-brain-derived oligomers have the potential to enhance the translational value from pre-clinical proof-of-concept studies to clinical trials.

Automated summary

In this study, we analyzed the concentration and size distribution of AD oligomers in different transgenic mouse models and in human brain samples. We demonstrated that the compound RD2 eliminated oligomers in mouse and human AD brain tissue, providing potential translational value from pre-clinical studies to clinical trials.