Amyloid aggregates are aging-related, symptomatically associated with Alzheimer's disease (AD), which is characterized by the presence of extracellular plaques, intracellular neurofibrillary tangles, and the loss of synapses and neurons in the brain of AD patients. Aggregation of disordered amyloidogenic, amyloid-� (A�) peptides into oligomers is the causative agent of AD. In solution, disordered protein states are characterized by heterogeneous ensembles. Among these, �-rich conformers self-assemble via a conformational selection mechanism to form energetically-favored cross-� structures, regardless of their precise sequences. These disordered A� peptides can also penetrate the membrane, and electrophysiological data indicate that they form ion-conducting channels. Based on these electrophysiology results and additional data from AFM imaging and molecular dynamics (MD) simulations of a range of amyloid peptides, including wild-type A� peptide, its disease-related variants with point mutations, and N-terminal truncated species, as well as other amyloidogenic peptides, such as cytolytic antimicrobial peptide (AMP) and a synthetic gel-forming peptide, we suggest that disordered amyloidogenic peptides can also present a common motif in the membrane. The motif consists of curved, moon-like �-rich oligomers associated into annular organizations. The motif is favored in the lipid bilayer since it permits hydrophobic side chains to face and interact with the membrane and the charged/polar residues to face the solvated channel pores. Such channels are toxic since their pores allow uncontrolled leakage of ions into/out of the cell, destabilizing cellular ionic homeostasis. This suggests that the �-sheet is a structure optimized for nonspecific pore formation. While the small highly selective and tightly regulated ion channels of nerve and muscle cells that mediate electrical excitability are  dominated by a-helical structures, it appears to be the case that toxic channel forming peptides rely more heavily on �-sheet structures.

Membrane insertion of Alzheimer's amyloid-� (A�) peptides and their assembly into common cyclic structural motifs

248th National Meeting (2014)

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