ABSTRACT
The elimination of amyloid beta (Aß) oligomers is a promising strategy for therapeutic drug development of Alzheimer's disease (AD). AD mouse models that develop Aß 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 Aß 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 Aß 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.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Humans , Mice , Mice, TransgenicABSTRACT
Oligomers of the amyloid-ß (Aß) protein are suspected to be responsible for the development and progression of Alzheimer's disease. Thus, the development of compounds that are able to eliminate already formed toxic Aß oligomers is very desirable. Here, we describe the in vivo efficacy of the compound RD2, which was developed to directly and specifically eliminate toxic Aß oligomers. In a truly therapeutic, rather than a preventive study, oral treatment with RD2 was able to reverse cognitive deficits and significantly reduce Aß pathology in old-aged transgenic Alzheimer's Disease mice with full-blown pathology and behavioral deficits. For the first time, we demonstrate the in vivo target engagement of RD2 by showing a significant reduction of Aß oligomers in the brains of RD2-treated mice compared to placebo-treated mice. The correlation of Aß elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice support the hypothesis that Aß oligomers are relevant not only for disease development and progression, but also offer a promising target for the causal treatment of Alzheimer's disease.
