The Aβ oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology

While amyloid-beta protein (A beta) aggregation into insoluble plaques is one of the pathological hallmarks of Alzheimer's disease (AD), soluble oligomeric A beta has been hypothesized to be responsible for synapse damage, neurodegeneration, learning, and memory deficits in AD. Here, we investigate the in vitro and in vivo efficacy of the D-enantiomeric peptide RD2, a rationally designed derivative of the previously described lead compound D3, which has been developed to efficiently eliminate toxic A beta 42 oligomers as a promising treatment strategy for AD. Besides the detailed in vitro characterization of RD2, we also report the results of a treatment study of APP/PS1 mice with RD2. After 28 days of treatment we observed enhancement of cognition and learning behaviour. Analysis on brain plaque load did not reveal significant changes, but a significant reduction of insoluble A beta 42. Our findings demonstrate that RD2 was significantly more efficient in A beta oligomer elimination in vitro compared to D3. Enhanced cognition without reduction of plaque pathology in parallel suggests that synaptic malfunction due to A beta oligomers rather than plaque pathology is decisive for disease development and progression. Thus, A beta oligomer elimination by RD2 treatment may be also beneficial for AD patients.