Atomic force microscopy and MD simulations reveal pore-like structures of all-D-enantiomer of Alzheimer's ?-amyloid peptide: relevance to the ion channel mechanism of AD pathology.

ABSTRACT: Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of ?-amyloid (A?) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves A? peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the A? peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the A? peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of A?-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length A?(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-A? isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-A?(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of A? ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through A? interaction with membrane receptors.

SUBMITTER: Connelly L 

PROVIDER: S-EPMC4342054 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature