Atomic force microscopy and MD simulations reveal pore-like structures of all-d-enantiomer of Alzheimer's β-amyloid peptide: Relevance to the ion channel mechanism of AD pathology

Laura Connelly, Hyunbum Jang, Fernando Teran Arce, Ricardo Capone, Samuel A. Kotler, Srinivasan Ramachandran, Bruce L. Kagan, Ruth Nussinov, Ratnesh Lal

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; l-amino acid peptides, but not their d-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like l-amino acids, d-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both d- and l-enantiomers of the full length Aβ 1-42 when reconstituted in lipid bilayers. AFM imaging shows that both l- and d-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that d-Aβ1-42 channels conduct ions similarly to their l- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors.

Original languageEnglish (US)
Pages (from-to)1728-1735
Number of pages8
JournalJournal of Physical Chemistry B
Volume116
Issue number5
DOIs
StatePublished - Feb 9 2012
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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