Ex vivo target engagement of the Abeta oligomer disassembling compound RD2 in patient derived brain homogenates

Abstract

BackgroundSoluble Aβ oligomers are highly toxic and may be responsible for development and progression of Alzheimer’s disease (AD). Elimination of Aβ oligomers is therefore a promising therapeutic strategy. The compound RD2 was developed to stabilize Aβ monomers in their native conformation, which is very close to an intrinsically disordered protein (IDP). RD2 has demonstrated already to directly eliminate soluble Aβ oligomers in vitro and in vivo and to improve cognition or decelerate neurodegeneration in four different animal models in four different laboratories 1,2. Here, we wanted to test if RD2 is able to disassemble Aβ oligomers obtained from AD patient derived brain tissue.MethodAβ oligomers in AD patient derived brain tissue homogenates were incubated with different concentrations of RD2 and control compounds. Aβ oligomer concentrations were determined longitudinally by the sFIDA assay, a single‐particle sensitive method for quantitating protein oligomers and aggregates.ResultRD2 concentration and incubation time‐dependent reduction of Aβ oligomers in brain homogenates was observed. Control compounds did not reduce Aβ oligomer concentrations.ConclusionThe incubation time and RD2 concentration dependent disassembly of Aβ oligomers from human brain homogenate suggest a very efficient ability of RD2 to fulfill its mode of action, namely the direct disassembly of Aβ oligomers into their Aβ monomer building blocks. Kinetic analysis and the mode of action resemble very much that of catalytic chaperones.