It used to be thought that Alzheimer's disease was caused by fibrils formed primarily by alyloid beta (Abeta) peptides of 40 or 42 residues. However, numerous recent studies indicate that smaller oligomeric assemblies of Abeta are responsible for inhibition of long-term potentiation associated with short-term memory loss, and for neurotoxic properties that cause cell death. Several recent studies also indicate that neurotoxity involves interactions with membranes and have supported initial findings of our collaborators that Abeta peptides form transmembrane ion channels. Abeta peptides form many different types of assemblies and even the secondary structure of the peptides depends upon its environment and concentration, and often changes with time. For example, solution NMR studies of Abeta monomers in apolar solvent studies have identified two a-helical segments; whereas, solid state NMR studies of fibrils indicate that the same two segments form a strands that assemble into parallel a sheets. The peptide assembly process that leads to fibrils is very slow, in some cases taking days to occur, and is preceded by formation of a variety of smaller oligomers and protofibrils. We are using molecular modeling and simulations to better understand the structures of these oligomers and how they assemble. We have constructed the following types of soluble assemblies: dimers, trimers, tetramers, hexamers, strings of hexamers, dodecamers, AbetaOs (18 subunits), annular protofibril (36 subunits), HMW oligomers (72 subunits), protofibrils with mass-per-lengths of 18 and 27kDa/nm, and two-dimensional hexagonal lattices that can extend indefinitely. We have also developed numerous models in which Abeta peptides form large assemblies on the membrane surface and then insert through the membrane to form channels. Assemblies with dimensions and masses of both soluble and membrane-bound models have been observed in microscopy and biochemical studies. Most of our models of the large assemblies involve hexamers in which the C-termini segments (residues 29-40 or 29-42) form a six-stranded antiparallel a barrel. We have also simulated how some of these assemblies could morph or grow into models of models of fibrils that are based on solid state NMR results. The PrP prion protein can exist in two forms, the normal PrPC form and a toxic PrPSc form that causes the Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, scrapie, and other spongiform encephalopathies. Aspects of the PrP and PrP-associated diseases resemble those of Abeta and Alzheimer's. The most hydrophobic portion of the 230 residue-long PrP protein has a sequence quite similar to the hydrophobic segment of Abeta that we propose to form a a barrel. PrPSc has been shown to assemble into a hexagonal lattice and into fibrils. We have constructed PrP models with the axis of the putative a barrel on one of the 3-fold axes of the lattice (similar to our hexagonal lattice models of Abeta). Experimental studies indicate that PrP protein can span membranes and may interact with Abeta peptides. We have constructed models in which the PrP a barrels span the lipid bilayer and in which a hexagonal lattice structure contains both PrP and Abeta.
