Selecting Multitarget Peptides for Alzheimer's Disease

Biomolecules. 2022 Sep 27;12(10):1386. doi: 10.3390/biom12101386.


Alzheimer's disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer's disease, by targeting both neuroinflammation and neurodegeneration.

Keywords: Alzheimer’s disease; S100 calcium-binding protein A9; Toll-like receptor 4; amyloid beta; cathepsin G; multitarget drug; neurodegeneration; neuroinflammation; neutrophil; receptor for advanced glycation end-products.

Publication types

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

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Calcium-Binding Proteins
  • Cathepsin G / metabolism
  • Humans
  • Mice
  • Receptor for Advanced Glycation End Products / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Trypan Blue


  • Amyloid beta-Peptides
  • Toll-Like Receptor 4
  • Receptor for Advanced Glycation End Products
  • Cathepsin G
  • Trypan Blue
  • Calcium-Binding Proteins