Truncated beta-amyloid peptide channels provide an alternative mechanism for Alzheimer's Disease and Down syndrome

Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6538-43. doi: 10.1073/pnas.0914251107. Epub 2010 Mar 22.

Abstract

Full-length amyloid beta peptides (Abeta(1-40/42)) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments (Abeta(11-42) and Abeta(17-42)) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Abeta(9-42) and Abeta(17-42) peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Abeta fragments could account for undefined roles played by full length Abetas and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.

Publication types

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

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / ultrastructure
  • Calcium / metabolism
  • Cell Death
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Humans
  • Microscopy, Atomic Force
  • Models, Molecular
  • Peptide Fragments / metabolism*
  • Peptide Fragments / ultrastructure
  • Protein Structure, Tertiary

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-peptide (9-42)
  • amyloid beta-protein (11-42)
  • amyloid beta-protein (17-42)
  • Calcium