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

Hyunbum Jang, Fernando Teran Arce, Srinivasan Ramachandran, Ricardo Capone, Rushana Azimova, Bruce L. Kagan, Ruth Nussinov, Ratnesh Lal

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

Full-length amyloid beta peptides (Aβ1-40/42) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in ADpathology.However, recent transgenic animalmodels castdoubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments (Aβ11-42 and Aβ17-42) 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 conductancemeasurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Aβ9-42 and Aβ17-42 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 Aβ fragments could account for undefined roles played by full length Aβs and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channelmechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.

Original languageEnglish (US)
Pages (from-to)6538-6543
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number14
DOIs
StatePublished - Apr 6 2010
Externally publishedYes

Keywords

  • Atomic force microscopy
  • Cell calcium imaging
  • Molecular dynamics
  • Neurite degeneration and cell death assays
  • Single-channel conductance

ASJC Scopus subject areas

  • General

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