Targeting Hsc70-based autophagy to eliminate amyloid β oligomers

Biochem Biophys Res Commun. 2020 Apr 16;524(4):923-928. doi: 10.1016/j.bbrc.2020.02.016. Epub 2020 Feb 11.


Amyloid β (Aβ) oligomers may be a real culprit in the pathogenesis of Alzheimer's disease (AD); therefore, the elimination of these toxic oligomers may be of great significance for AD therapy. Autophagy is the catabolic process by which lysosomes degrade cytosolic components, and heat shock cognate 70 kDa protein (Hsc70) binds to proteins with their KFERQ-like motifs [also known as chaperone-mediated autophagy (CMA) motifs] and carries them to lysosomes through CMA or late endosomes through endosomal microautophagy (eMI) for degradation. In this study, our strategy is to make the pathological Aβ become one selective and suitable substrate for CMA and eMI (termed as Hsc70-based autophagy) by tagging its oligomers with multiple CMA motifs. First, we design and synthesize Aβ oligomer binding peptides with three CMA motifs. Second, we determine that the peptide can help Aβ oligomers enter endosomes and lysosomes, which can be further enhanced by ketone. More importantly, we find that the peptide can dramatically reduce Aβ oligomers in induced pluripotent stem cell (iPSC) cortical neurons derived from AD patient fibroblasts and protect primary cultured cortical neurons against the Aβ oligomer-induced neurotoxicity. In conclusion, we demonstrate that the peptide targeting Hsc70-based autophagy can effectively eliminate Aβ oligomers and have superior neuroprotective activity.

Keywords: Alzheimer’s disease; Aβ oligomers; Chaperone-mediated autophagy; Hsc70.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy
  • Amino Acid Motifs
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Cell Differentiation
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Chaperone-Mediated Autophagy / drug effects*
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • HSC70 Heat-Shock Proteins / genetics
  • HSC70 Heat-Shock Proteins / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Molecular Targeted Therapy
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / pharmacology*
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Primary Cell Culture
  • Protein Binding
  • Proteolysis
  • Rats
  • Rats, Long-Evans


  • Amyloid beta-Peptides
  • HSC70 Heat-Shock Proteins
  • Neuroprotective Agents
  • Peptides