Evidence that Perutz's double-beta-stranded subunit structure for beta-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-beta-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 beta-amyloids. One strong criterion for the stability of the Perutz structure for an amyloid is that it contain approximately 40 or more amino acid residues. We show here that the neurotoxic Abeta amyloids 1-40 and 1-42, related to Alzheimer's disease, spontaneously enter the membranes of intact erythrocytes and cause their lysis but that Abeta 1-38 and Abeta 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 beta-amyloids are explored.
Singer
S Jonathan
SJ
Division of Biological Sciences, Department of Medicine, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. ssinger@ucsd.edu
Dewji
Nazneen N
NN
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D004912:Erythrocytes / Q000378:metabolism; D006860:Hydrogen Bonding; D008051:Lipid Bilayers / Q000737:chemistry; D008958:Models, Molecular; D019636:Neurodegenerative Diseases; D009474:Neurons / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D012984:Software; D013997:Time Factors; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D009842:Oligopeptides; D010455:Peptides; D014867:Water; C097188:polyglutamine