title: 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 Aβ1-42forms ion channel structures in BTLE membranes, accompanied by a heterogeneous population of ionic current fluctuations. Notably, the observed current events generated by Aβ1-42peptides in BTLE membranes possess different characteristics compared to current events generated by the presence of Aβ1-42in 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 Aβ1-42in BTLE membranes. However, the observed macroscopic ion flux across the BTLE membranes induced by Aβ1-42pores 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.
authors.forename: Joon
authors.identifier: 0000-0003-3887-8540
authors.initials: J
authors.lastname: Lee
authors.forename: Young Hun
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Division of Translational and Regenerative Medicine, Department of Medicine, Department of Biomedical Engineering, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Fernando
authors.initials: F
authors.lastname: T Arce
authors.forename: Alan L
authors.identifier: 0000-0002-1312-047X
authors.initials: AL
authors.lastname: Gillman
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California , Los Angeles, California 90024, United States.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Kagan
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute at Frederick, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Jerry
authors.identifier: 0000-0002-8423-7376
authors.initials: J
authors.lastname: Yang
authors.forename: Ratnesh
authors.initials: R
authors.lastname: Lal
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D007473:Ion Channels; D008051:Lipid Bilayers; D008563:Membrane Lipids
keywords: Alzheimer’s disease; amyloid channels; amyloid β peptides; amyloid−membrane interactions; atomic force microscopy; black lipid membrane electrophysiology; brain total lipid extract