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

Wenkang Zhang; Guanbin Gao; Zhongjie Ma; Zhuoying Luo; Meng He; Taolei Sun

doi:10.1093/nsr/nwz215

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

Natl Sci Rev. 2020 Apr;7(4):763-774. doi: 10.1093/nsr/nwz215. Epub 2019 Dec 20.

Authors

Wenkang Zhang¹, Guanbin Gao¹, Zhongjie Ma¹, Zhuoying Luo¹, Meng He², Taolei Sun^{1

2}

Affiliations

¹ State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, China.
² School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, China.

Abstract

The misfolding of amyloid-β (Aβ) peptides from the natural unfolded state to β-sheet structure is a critical step, leading to abnormal fibrillation and formation of endogenous Aβ plaques in Alzheimer's disease (AD). Previous studies have reported inhibition of Aβ fibrillation or disassembly of exogenous Aβ fibrils in vitro. However, soluble Aβ oligomers have been reported with increased cytotoxicity; this might partly explain why current clinical trials targeting disassembly of Aβ fibrils by anti-Aβ antibodies have failed so far. Here we show that Au₂₃(CR)₁₄ (a new Au nanocluster modified by Cys-Arg (CR) dipeptide) is able to completely dissolve exogenous mature Aβ fibrils into monomers and restore the natural unfolded state of Aβ peptides from misfolded β-sheets. Furthermore, the cytotoxicity of Aβ₄₀ fibrils when dissolved by Au₂₃(CR)₁₄ is fully abolished. More importantly, Au₂₃(CR)₁₄ is able to completely dissolve endogenous Aβ plaques in brain slices from transgenic AD model mice. In addition, Au₂₃(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.

Keywords: Alzheimer's disease; abolished cytotoxicity; dissolves endogenous Aβ plaques; gold nanoclusters; restores fibril Aβ’s unfolded state.