Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro

Molecular chaperones play important roles in preventing protein misfolding and its potentially harmful consequences. Deterioration of molecular chaperone systems upon ageing are thought to underlie age-related neurodegenerative diseases, and augmenting their activities could have therapeutic potential. The dementia relevant domain BRICHOS from the Bri2 protein shows qualitatively different chaperone activities depending on quaternary structure, and assembly of monomers into high-molecular weight oligomers reduces the ability to prevent neurotoxicity induced by the Alzheimer-associated amyloid-beta peptide 1-42 (A beta 42). Here we design a Bri2 BRICHOS mutant (R221E) that forms stable monomers and selectively blocks a main source of toxic species during A beta 42 aggregation. Wild type Bri2 BRICHOS oligomers are partly disassembled into monomers in the presence of the R221E mutant, which leads to potentiated ability to prevent A beta 42 toxicity to neuronal network activity. These results suggest that the activity of endogenous molecular chaperones may be modulated to enhance anti-A beta 42 neurotoxic effects. Gefei Chen et al. show that a mutated BRICHOS molecular chaperone domain from the dementia associated Bri2 can reduce toxicity of amyloid formation in mouse hippocampus in vitro. Upon mutating Arg221 to glutamate, Bri2 BRICHOS forms stable monomers that block a source of neurotoxicity during A beta aggregation and promote disassembly of wild-type oligomers.