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

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 comprised of 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.

Theory of concentric β-barrel structures: models of amyloid beta 42 oligomers, annular protofibrils, and transmembrane channels

“…N-terminus truncation variants 1-x, 3-x, 11-x, and 17-x have been assessed in human amyloid plaques, and N-terminal truncation (probably 17x) appears to be involved in early amyloid pathology in Down's Syndrome 53 . Synthesized 17x Aβ peptides form channels in lipid bilayers 54 , but it is not known whether they form channels in excised neuronal patches, and if so whether these channels have the same conductance properties as WT Aβ42 channels.…”

Amyloids: Regulators of Metal Homeostasis in the Synapse

“…Voelker et al demonstrated that AβP(1-40) as well as AβP(1-42) formed trimers to pentamers that could form ion channels in water [121]. AβPs were shown to form pores by high resolution atomic force microscopy (AFM) as well [122]. Lee et al observed the formation of AβP channels on membranes from brain total lipid extracts using AFM [123].…”

The Interaction between Amyloid Prefibrillar Oligomers of Salmon Calcitonin and a Lipid-Raft Model: Molecular Mechanisms Leading to Membrane Damage, Ca2+-Influx and Neurotoxicity

“…Notably, a common molecular mechanism of pore formation by Aβ and α-sin involving gangliosides and cholesterol (Chol) has been proposed by Di Scala et al [23]. More recently, Lee et al reported on ion channels formed by Aβ in membranes comprising brain total lipid extract [24].…”