Evidence that Perutz's double-β-stranded subunit structure for β-amyloids also applies to their channel-forming structures in membranes

Although there is a growing body of evidence that different amyloidoses may have a similar molecular mechanism in common, the many details of this mechanism are not understood. In this study, we propose that there is a common molecular structure of the primary agents of these diseases, namely a small oligomer of Perutz's cylindrical double-β-stranded subunit for polyglutamine and that this structure, which contains a central water-filled core, can spontaneously integrate into the bilayers of membranes to form aqueous pores. We suggest that this ability to produce permeable channels in appropriate neuronal membranes is a key element in the toxicity of the β-amyloids. One strong criterion for the stability of the Perutz structure for an amyloid is that it contain ≈40 or more amino acid residues. We show here that the neurotoxic Aβ amyloids 1-40 and 1-42, related to Alzheimer's disease, spontaneously enter the membranes of intact erythrocytes and cause their lysis but that Aβ 1-38 and Aβ 1-35, which are not neurotoxic, have no observable effects on erythrocytes, supporting our proposal. Other aspects of the proposed mechanism of cytotoxicity of the β-amyloids are explored.

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