8-20 Fragment as an Anti-Fibrillogenic and Neuroprotective Agent: Advancing toward Efficient Alzheimer's Disease Treatment

ACS Chem Neurosci. 2023 Mar 15;14(6):1126-1136. doi: 10.1021/acschemneuro.2c00720. Epub 2023 Mar 1.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, characterized by a spectrum of symptoms associated with memory loss and cognitive decline with deleterious consequences in everyday life. The lack of specific drugs for the treatment and/or prevention of this pathology makes AD an ever-increasing economic and social emergency. Oligomeric species of amyloid-beta (Aβ) are recognized as the primary cause responsible for synaptic dysfunction and neuronal degeneration, playing a crucial role in the onset of the pathology. Several studies have been focusing on the use of small molecules and peptides targeting oligomeric species to prevent Aβ aggregation and toxicity. Among them, peptide fragments derived from the primary sequence of Aβ have also been used to exploit any eventual recognition abilities toward the full-length Aβ parent peptide. Here, we test the Aβ8-20 fragment which contains the self-recognizing Lys-Leu-Val-Phe-Phe sequence and lacks Arg 5 and Asp 7 and the main part of the C-terminus, key points involved in the aggregation pathway and stabilization of the fibrillary structure of Aβ. In particular, by combining chemical and biological techniques, we show that Aβ8-20 does not undergo random coil to β sheet conformational transition, does not form amyloid fibrils by itself, and is not toxic for neuronal cells. Moreover, we demonstrate that Aβ8-20 mainly interacts with the 4-11 region of Aβ1-42 and inhibits the formation of toxic oligomeric species and Aβ fibrils. Finally, our data show that Aβ8-20 protects neuron-like cells from Aβ1-42 oligomer toxicity. We propose Aβ8-20 as a promising drug candidate for the treatment of AD.

Keywords: Alzheimer; anti-aggregation; fibrils; oligomers.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism
  • Humans
  • Neuroprotective Agents* / pharmacology
  • Neuroprotective Agents* / therapeutic use
  • Peptide Fragments / metabolism

Substances

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