Atomic force microscopy and MD simulations reveal pore-like structures of all-D-enantiomer of Alzheimer's β-amyloid peptide: relevance to the ion channel mechanism of AD pathology.
Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-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 Aβ(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-Aβ(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors.
Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA.
Laura
L
Connelly
Hyunbum
H
Jang
Fernando Teran
FT
Arce
Ricardo
R
Capone
Samuel A
SA
Kotler
Srinivasan
S
Ramachandran
Bruce L
BL
Kagan
Ruth
R
Nussinov
Ratnesh
R
Lal
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D006801:Humans; D007536:Isomerism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)