Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum.
Amyloid beta protein (A beta P) 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 A beta P forms channels, which generate linear current-voltage relationships in symmetrical solutions. A permeability ratio, PK/PCl, of 11 for the open A beta P channel was estimated from the reversal potential of the channel current in asymmetrical KCl solutions. The permeability sequence for different cations, estimated from the reversal potential of the A beta P-channel current for each system of asymmetrical solutions, is Pcs > PLi > PCa > or = PK > PNa. A beta P-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 A beta P-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 A beta P channel. Hitherto, A beta P 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 A beta P channels.
Laboratory of Cell Biology and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
N
N
Arispe
E
E
Rojas
H B
HB
Pollard
D000535:Aluminum / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002412:Cations / Q000378:metabolism; D004553:Electric Conductivity; D006801:Humans; D008051:Lipid Bilayers; D008564:Membrane Potentials / Q000502:physiology; D010539:Permeability; D010718:Phosphatidylserines; D014325:Tromethamine / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D002412:Cations; D008051:Lipid Bilayers; D010718:Phosphatidylserines; D014325:Tromethamine; D000535:Aluminum; D002118:Calcium