In vivo induction of membrane damage by β-amyloid peptide oligomers

Acta Neuropathol Commun. 2018 Nov 29;6(1):131. doi: 10.1186/s40478-018-0634-x.


Exposure to the β-amyloid peptide (Aβ) is toxic to neurons and other cell types, but the mechanism(s) involved are still unresolved. Synthetic Aβ oligomers can induce ion-permeable pores in synthetic membranes, but whether this ability to damage membranes plays a role in the ability of Aβ oligomers to induce tau hyperphosphorylation, or other disease-relevant pathological changes, is unclear. To examine the cellular responses to Aβ exposure independent of possible receptor interactions, we have developed an in vivo C. elegans model that allows us to visualize these cellular responses in living animals. We find that feeding C. elegans E. coli expressing human Aβ induces a membrane repair response similar to that induced by exposure to the CRY5B, a known pore-forming toxin produced by B. thuringensis. This repair response does not occur when C. elegans is exposed to an Aβ Gly37Leu variant, which we have previously shown to be incapable of inducing tau phosphorylation in hippocampal neurons. The repair response is also blocked by loss of calpain function, and is altered by loss-of-function mutations in the C. elegans orthologs of BIN1 and PICALM, well-established risk genes for late onset Alzheimer's disease. To investigate the role of membrane repair on tau phosphorylation directly, we exposed hippocampal neurons to streptolysin O (SLO), a pore-forming toxin that induces a well-characterized membrane repair response. We find that SLO induces tau hyperphosphorylation, which is blocked by calpain inhibition. Finally, we use a novel biarsenical dye-tagging approach to show that the Gly37Leu substitution interferes with Aβ multimerization and thus the formation of potentially pore-forming oligomers. We propose that Aβ-induced tau hyperphosphorylation may be a downstream consequence of induction of a membrane repair process.

Keywords: Alzheimer’s disease; Caenorhabditis elegans; Pore-forming toxin; Tau; β-amyloid.

Publication types

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

MeSH terms

  • Acrylates / pharmacology
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Animals, Genetically Modified
  • Bacillus thuringiensis Toxins
  • Bacterial Proteins / toxicity
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cells, Cultured
  • Embryo, Mammalian
  • Endosomes / drug effects*
  • Endosomes / metabolism
  • Endotoxins / toxicity
  • Enzyme Inhibitors / pharmacology
  • Hemolysin Proteins / toxicity
  • Hippocampus / cytology
  • Humans
  • Intestines / cytology
  • Intestines / drug effects
  • Models, Animal
  • Morpholinos / pharmacology
  • Neurons / drug effects*
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity*
  • Phosphorylation / drug effects
  • Rats
  • Sphingomyelin Phosphodiesterase / pharmacology
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • Wound Healing / drug effects


  • Acrylates
  • Amyloid beta-Peptides
  • Bacillus thuringiensis Toxins
  • Bacterial Proteins
  • Caenorhabditis elegans Proteins
  • Endotoxins
  • Enzyme Inhibitors
  • Hemolysin Proteins
  • Morpholinos
  • PD 150606
  • Peptide Fragments
  • Rab-5 protein, C elegans
  • Vesicular Transport Proteins
  • amyloid beta-protein (1-42)
  • insecticidal crystal protein, Bacillus Thuringiensis
  • Sphingomyelin Phosphodiesterase