Alzheimer amyloid abeta1-42 channels: effects of solvent, pH, and Congo Red.
Substantial genetic and biochemical evidence implicates amyloid peptides (Abeta) in the etiology of Alzheimer's Disease (AD). Recent evidence indicates that Abeta1-42 is the predominant species in the hallmark senile amyloid plaque of AD. Furthermore, Abeta1-42 forms aggregates inside lysosomes of cultured neurons leading to lysosomal disruption and cell death. We report here that Abeta1-42 forms slightly cation selective, voltage-independent ion channels with multiple conductance levels at neurotoxic concentrations in planar bilayer membranes. The channels show substantial irregularity of activity, and the size of conductances and the length of open lifetimes depend on solvent history. Formation of channels requires anionic lipids, is enhanced in acidic solutions, and is inhibited by Congo Red. These properties suggest that the channels are formed by aggregates of Abeta1-42. In addition, the channels are reversibly blocked by zinc in a voltage-independent manner. The properties of these channels would likely render them neurotoxic to relevant neurons in vivo. These results are consistent with the channel hypothesis of Abeta neurotoxicity.
Hirakura
Y
Y
Department of Psychiatry and Biobehavioral Sciences, UCLA Neuropsychiatric Institute, Mental Retardation Research Center, Los Angeles, California 90024-1759, USA.
Lin
M C
MC
Kagan
B L
BL
D016229:Amyloid beta-Peptides / Q000187:drug effects*; D004396:Coloring Agents; D003224:Congo Red / Q000633:toxicity*; D004553:Electric Conductivity; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000187:drug effects*; D008051:Lipid Bilayers; D009498:Neurotoxins / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000187:drug effects*; D012997:Solvents; D015032:Zinc / Q000502:physiology
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D007473:Ion Channels; D008051:Lipid Bilayers; D009498:Neurotoxins; D010446:Peptide Fragments; D012997:Solvents; C075222:amyloid beta-protein (1-42); D003224:Congo Red; D015032:Zinc