Au23(CR)14 nanocluster restores fibril Aβ's unfolded state with abolished cytotoxicity and dissolves endogenous Aβ plaques

The misfolding of amyloid-beta (A beta) peptides from the natural unfolded state to beta-sheet structure is a critical step, leading to abnormal fibrillation and formation of endogenous A beta plaques in Alzheimer's disease (AD). Previous studies have reported inhibition of A beta fibrillation or disassembly of exogenous A beta fibrils in vitro. However, soluble A beta oligomers have been reported with increased cytotoxicity; this might partly explain why current clinical trials targeting disassembly of A beta fibrils by anti-A beta antibodies have failed so far. Here we show that Au-23(CR)(14) (a new Au nanocluster modified by Cys-Arg (CR) dipeptide) is able to completely dissolve exogenous mature A beta fibrils into monomers and restore the natural unfolded state of A beta peptides from misfolded beta-sheets. Furthermore, the cytotoxicity of A beta(40) fibrils when dissolved by Au-23(CR)(14) is fully abolished. More importantly, Au-23(CR)(14) is able to completely dissolve endogenous A beta plaques in brain slices from transgenic AD model mice. In addition, Au-23(CR)(14) has good biocompatibility and infiltration ability across the blood-brain barrier. Taken together, this work presents a promising therapeutics candidate for AD treatment, and manifests the potential of nanotechnological approaches in the development of nanomedicines.