APPI-Derived Cyclic Peptide Enhances Aβ42 Aggregation and Reduces Aβ42-Mediated Membrane Destabilization and Cytotoxicity

Shiran Lacham-Hartman, Reut Moshe, Shani Ben-Zichri, Yulia Shmidov, Ronit Bitton, Raz Jelinek, Niv Papo

Research output: Contribution to journalArticlepeer-review


An amyloid precursor protein inhibitor (APPI) and amyloid beta 42 (Aβ42) are both subdomains of the human transmembrane amyloid precursor protein (APP). In the brains of patients with Alzheimer’s disease (AD), Aβ42 oligomerizes into aggregates of various sizes, with intermediate, low-molecular-weight Aβ42 oligomers currently being held to be the species responsible for the most neurotoxic effects associated with the disease. Strategies to ameliorate the toxicity of these intermediate Aβ42 oligomeric species include the use of short, Aβ42-interacting peptides that either inhibit the formation of the Aβ42 oligomeric species or promote their conversion to high-molecular-weight aggregates. We therefore designed such an Aβ42-interacting peptide that is based on the β-hairpin amino acid sequence of the APPI, which exhibits high similarity to the β-sheet-like aggregation site of Aβ42. Upon tight binding of this 20-mer cyclic peptide to Aβ42 (in a 1:1 molar ratio), the formation of Aβ42 aggregates was enhanced, and consequently, Aβ42-mediated cell toxicity was ameliorated. We showed that in the presence of the cyclic peptide, interactions of Aβ42 with both plasma and mitochondrial membranes and with phospholipid vesicles that mimic these membranes were inhibited. Specifically, the cyclic peptide inhibited Aβ42-mediated mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. We suggest that the cyclic peptide modulates Aβ42 aggregation by enhancing the formation of large aggregates─as opposed to low-molecular-weight intermediates─and as such has the potential for further development as an AD therapeutic.

Original languageEnglish
Pages (from-to)3385-3397
Number of pages13
JournalACS Chemical Neuroscience
Issue number18
StatePublished - 20 Sep 2023


  • APPI
  • Alzheimer’s disease
  • Aβ42
  • artificial membranes
  • neuronal cell toxicity
  • peptide−lipid interactions

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Biochemistry
  • Physiology
  • Cell Biology


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