Amyloid β Ion Channels in a Membrane Comprising Brain Total Lipid Extracts

Joon Lee, Young Hun Kim, Fernando Arce, Alan L. Gillman, Hyunbum Jang, Bruce L. Kagan, Ruth Nussinov, Jerry Yang, Ratnesh Lal

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Amyloid β (Aβ) oligomers are the predominant toxic species in the pathology of Alzheimer's disease. The prevailing mechanism for toxicity by Aβ oligomers includes ionic homeostasis destabilization in neuronal cells by forming ion channels. These channel structures have been previously studied in model lipid bilayers. In order to gain further insight into the interaction of Aβ oligomers with natural membrane compositions, we have examined the structures and conductivities of Aβ oligomers in a membrane composed of brain total lipid extract (BTLE). We utilized two complementary techniques: atomic force microscopy (AFM) and black lipid membrane (BLM) electrical recording. Our results indicate that Aβ1-42 forms ion channel structures in BTLE membranes, accompanied by a heterogeneous population of ionic current fluctuations. Notably, the observed current events generated by Aβ1-42 peptides in BTLE membranes possess different characteristics compared to current events generated by the presence of Aβ1-42 in model membranes comprising a 1:1 mixture of DOPS and POPE lipids. Oligomers of the truncated Aβ fragment Aβ17-42 (p3) exhibited similar ion conductivity behavior as Aβ1-42 in BTLE membranes. However, the observed macroscopic ion flux across the BTLE membranes induced by Aβ1-42 pores was larger than for p3 pores. Our analysis of structure and conductance of oligomeric Aβ pores in a natural lipid membrane closely mimics the in vivo cellular environment suggesting that Aβ pores could potentially accelerate the loss of ionic homeostasis and cellular abnormalities. Hence, these pore structures may serve as a target for drug development and therapeutic strategies for AD treatment.

Original languageEnglish (US)
Pages (from-to)1348-1357
Number of pages10
JournalACS Chemical Neuroscience
Volume8
Issue number6
DOIs
StatePublished - Jun 21 2017

Keywords

  • Alzheimer's disease
  • amyloid channels
  • amyloid β peptides
  • amyloid-membrane interactions
  • atomic force microscopy
  • black lipid membrane electrophysiology
  • brain total lipid extract

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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