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β-amyloid Ca2+-channel hypothesis for neuronal death in Alzheimer Disease

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Abstract

The Alzheimer's Disease (AD) amyloid protein (AßP[1-40]) forms cation selective channels when incorporated into planar lipid bilayers by fusion with liposomes containing the peptide. Since the peptide has been proposed to occurin vivo in both membrane-bound and soluble forms, we also tested the possibility of direct incorporation of the soluble AßP[1-40] into the membrane. We found the peptide can also form similar channels in acidic phospholipid bilayers formed at the tip of a patch pipet, as well as in the planar lipid bilayer system. As in the case of liposome mediated incorporation, the AßP[1-40]-channel in the solvent-free membrane patch exhibits multiple cation selectivity (Cs+>Li+>Ca2+≥K+) and sensitivity to tromethamine. The fact that equivalentAßP[1-40] amyloid channels can be detected by two different methods thus provides additional validation of our original observation. Further studies with aßP-channels incorporated into planar lipid bilayers from the liposome complex have also revealed that the channel activity can express spontaneous transitions to a much higher range of conductances between 400 and 4000 pS. Under these conditions, the amyloid channel continues to be cation selective but loses its tromethamine sensitivity. By contrast, amyloid channels were insensitive to nitrendipine at either conductance range. We calculate that if such channels were expressed in cells, the ensuing ion fluxes down their electrochemical potential gradients would disrupt cellular homeostasis. We therefore interpret these data as providing further support for our ß-amyloid Ca2+-channel hypothesis for neuronal death in Alzheimer's Disease.

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Authors and Affiliations

  1. Laboratory of Cell Biology and Genetics, NIDDK, National Institutes of Health, 20892, Bethesda, MD, USA

    Nelson Arispe, Harvey B. Pollard & Eduardo Rojas

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  1. Nelson Arispe
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  2. Harvey B. Pollard
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  3. Eduardo Rojas
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Arispe, N., Pollard, H.B. & Rojas, E. β-amyloid Ca2+-channel hypothesis for neuronal death in Alzheimer Disease. Mol Cell Biochem 140, 119–125 (1994). https://doi.org/10.1007/BF00926750

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