Brain Hydrophobic Peptides Antagonists of Neurotoxic Amyloid β Peptide Monomers/Oligomers-Protein Interactions

Abstract

Amyloid β (Aβ) oligomers have been linked to Alzheimer's disease (AD) pathogenesis and are the main neurotoxic forms of Aβ. This review focuses on the following: (i) the Aβ(1-42):calmodulin interface as a model for the design of antagonist Aβ peptides and its limitations; (ii) proteolytic degradation as the major source of highly hydrophobic peptides in brain cells; and (iii) brain peptides that have been experimentally demonstrated to bind to Aβ monomers or oligomers, Aβ fibrils, or Aβ plaques. It is highlighted that the hydrophobic amino acid residues of the COOH-terminal segment of Aβ(1-42) play a key role in its interaction with intracellular protein partners linked to its neurotoxicity. The major source of highly hydrophobic endogenous peptides of 8-10 amino acids in neurons is the proteasome activity. Many canonical antigen peptides bound to the major histocompatibility complex class 1 are of this type. These highly hydrophobic peptides bind to Aβ and are likely to be efficient antagonists of the binding of Aβ monomers/oligomers concentrations in the nanomolar range with intracellular proteins. Also, their complexation with Aβ will protect them against endopeptidases, suggesting a putative chaperon-like physiological function for Aβ that has been overlooked until now. Remarkably, the hydrophobic amino acid residues of Aβ responsible for the binding of several neuropeptides partially overlap with those playing a key role in its interaction with intracellular protein partners that mediates its neurotoxicity. Therefore, these latter neuropeptides are also potential candidates to antagonize Aβ peptides binding to target proteins. In conclusion, the analysis performed in this review points out that hydrophobic endogenous brain neuropeptides could be valuable biomarkers to evaluate the risk of the onset of sporadic AD, as well as for the prognosis of AD.

Keywords: Alzheimer’s disease; amyloid β; calmodulin; canonical antigen peptides; endogenous hydrophobic peptides; neuropeptides; neurotoxicity; proteasome.

Figure 1

Scheme of Aβ oligomers (AβO) dynamics and neurotoxicity. AβO_e and AβO_i means AβO extracellular and intracellular, respectively. Generation of neurotoxic AβO are marked by red arrows. Black arrows are used for molecular mechanisms that attenuate the toxicity of AβO, stressing the protection that can be afforded by their complexation with endogenous antagonist Aβ peptides (AntPep).

Figure 2

Hydrophobicity plot of Aβ(1–42) segment 29–42 (blue) and of the designed peptide VFAFAMAFML (orange). The NH₂-terminus amino acid residue of the peptide VFAFAMAFML has been aligned with the amino acid residue 31 of Aβ(1–42).