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Alzheimer Disease Amyloid β Protein Forms Calcium Channels in Bilayer Membranes: Blockade by Tromethamine and Aluminum
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Alzheimer Disease Amyloid β Protein Forms Calcium Channels in Bilayer Membranes: Blockade by Tromethamine and Aluminum
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Journal Article
Alzheimer Disease Amyloid β Protein Forms Calcium Channels in Bilayer Membranes: Blockade by Tromethamine and Aluminum
1993
Overview
Amyloid β protein (AβP) is the 40- to 42-residue polypeptide implicated in the pathogenesis of Alzheimer disease. We have incorporated this peptide into phosphatidylserine liposomes and then fused the liposomes with a planar bilayer. When incorporated into bilayers the AβP forms channels, which generate linear current-voltage relationships in symmetrical solutions. A permeability ratio, PK/PCI, of 11 for the open AβP channel was estimated from the reversal potential of the channel current in asymmetrical KCI solutions. The permeability sequence for different cations, estimated from the reversal potential of the AβP-channel current for each system of asymmetrical solutions, is PCs> PLi> PCa≥ PK> PNa. AβP-channel current (either Cs+or Ca2+as charge carriers) is blocked reversibly by tromethamine (millimolar range) and irreversibly by Al3+(micromolar range). The inhibition of the AβP-channel current by these two substances depends on transmembrane potential, suggesting that the mechanism of blockade involves direct interaction between tromethamine (or Al3+) and sites within the AβP channel. Hitherto, AβP has been presumed to be neurotoxic. On the basis of the present data we suggest that the channel activity of the polypeptide may be responsible for some or all of its neurotoxic effects. We further propose that a useful strategy for drug discovery for treatment of Alzheimer disease may include screening compounds for their ability to block or otherwise modify AβP channels.
Publisher
National Academy of Sciences of the United States of America,National Acad Sciences
Subject
/ Aluminum
/ Alzheimer Disease - etiology
/ Amyloid beta-Peptides - drug effects
/ Amyloid beta-Peptides - metabolism
/ Amyloids
/ Biological and medical sciences
/ calcium
/ Calcium Channels - drug effects
/ Calcium Channels - metabolism
/ channels
/ Humans
/ Membrane Potentials - physiology
/ Nervous system involvement in other diseases. Miscellaneous
