The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide

PLoS One. 2010 Mar 3;5(3):e9505. doi: 10.1371/journal.pone.0009505.

Abstract

Background: The amyloid beta-protein (Abeta) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Abeta is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Abeta has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities.

Methodology/principal findings: Here, we provide data supporting an in vivo function for Abeta as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Abeta and LL-37, an archetypical human AMP. Findings reveal that Abeta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Abeta levels. Consistent with Abeta-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Abeta antibodies.

Conclusions/significance: Our findings suggest Abeta is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Abeta-mediated pathology and has important implications for ongoing and future AD treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / physiology*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Brain / pathology
  • Candida albicans / metabolism
  • Cell Survival
  • Environment
  • Humans
  • Immunity, Innate
  • Inflammation
  • Ligands
  • Microbial Sensitivity Tests
  • Oxazines / pharmacology
  • Recombinant Proteins / chemistry
  • Xanthenes / pharmacology

Substances

  • Amyloid beta-Peptides
  • Antimicrobial Cationic Peptides
  • Ligands
  • Oxazines
  • Recombinant Proteins
  • Xanthenes
  • CAP18 lipopolysaccharide-binding protein
  • resazurin