Identification of prion protein-derived peptides of potential use in Alzheimer's disease therapy

Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt A):2143-2153. doi: 10.1016/j.bbadis.2018.03.023. Epub 2018 Mar 28.


Soluble form of the prion protein (PrP) has been previously shown to interact with amyloid-β (Aβ) peptides, suppressing their fibrillization as well as toxicity, which indicates that this protein may play a protective role in Alzheimer's disease (AD). The shortest known PrP fragment retaining all of these properties corresponds to physiologically generated proteolytic polypeptide PrP23-110/111, called N1. Here we have identified two N1-derived synthetic peptides, encompassing residues 23-50 (PrP23-50) and 90-112 (PrP90-112), which bind to Aβ1-42 protofibrillar oligomers as well as amyloid fibrils. We found that, akin to N1, the abovementioned synthetic peptides not only reduce the initial rate of Aβ fibrillization, but also alter the aggregation pathway of Aβ, inhibiting formation of protofibrillar oligomers and facilitating amorphous aggregation. Furthermore, our data show that N1, PrP23-50 and PrP90-112 protect cultured hippocampal neurons from neurotoxic effects of Aβ oligomers, preventing oligomers-induced retraction of neurites and loss of cell membrane integrity. The above PrP fragments can also attenuate neuronal intake of Aβ. Our results strongly suggest that synthetic peptides such as PrP23-50 and PrP90-112 can be useful in designing a novel class of therapeutics in AD.

Keywords: Alzheimer's disease; Amyloid; Aβ peptide; Neurotoxicity; Prion protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Amyloid / metabolism
  • Amyloid / toxicity
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / pathology
  • Cells, Cultured
  • Hippocampus / cytology
  • Neurites / drug effects
  • Neurites / pathology
  • Neurofibrillary Tangles / drug effects*
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / pharmacology*
  • Peptide Fragments / therapeutic use
  • PrPC Proteins / chemistry
  • Primary Cell Culture
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / pathology
  • Rats
  • Rats, Wistar


  • Amyloid
  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Peptide Fragments
  • PrPC Proteins