Amyloid-beta-induced ion flux in artificial lipid bilayers and neuronal cells: resolving a controversy.
Understanding the pathogenicity of amyloid-beta (Abeta) peptides constitutes a major goal in research on Alzheimer's disease (AD). One hypothesis entails that Abeta peptides induce uncontrolled, neurotoxic ion flux through cellular membranes. The exact biophysical mechanism of this ion flux is, however, a subject of an ongoing controversy which has attenuated progress toward understanding the importance of Abeta-induced ion flux in AD. The work presented here addresses two prevalent controversies regarding the nature of transmembrane ion flux induced by Alphabeta peptides. First, the results clarify that Alphabeta can induce stepwise ion flux across planar lipid bilayers as opposed to a gradual increase in transmembrane current; they show that the previously reported gradual thinning of membranes with concomitant increase in transmembrane current arises from residues of the solvent hexafluoroisopropanol, which is commonly used for the preparation of amyloid samples. Second, the results provide additional evidence suggesting that Abeta peptides can induce ion channel-like ion flux in cellular membranes that is independent from the postulated ability of Alphabeta to modulate intrinsic cellular ion channels or transporter proteins.
Capone
Ricardo
R
Department of Biomedical Engineering, University of Michigan, 1101 Beal Ave, Ann Arbor, MI 48109-2110, USA.
Quiroz
Felipe Garcia
FG
Prangkio
Panchika
P
Saluja
Inderjeet
I
Sauer
Anna M
AM
Bautista
Mahealani R
MR
Turner
Raymond S
RS
Yang
Jerry
J
Mayer
Michael
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001703:Biophysics; D002462:Cell Membrane / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects*; D007477:Ions / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008567:Membranes, Artificial; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics; D020005:Propanols / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007477:Ions; D008051:Lipid Bilayers; D008567:Membranes, Artificial; D010446:Peptide Fragments; D053764:Presenilin-1; D020005:Propanols; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated