β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels

Abstract

Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small β-amyloid (Aβ) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis. Solid-state NMR-based data of amyloid oligomers in solution indicate that they consist of a double-layered β-sheets where each monomer folds into β-strand-turn-β-strand and the monomers are stacked atop each other. In the membrane, Aβ peptides are proposed to be β-type structures. Experimental structural data available from atomic force microscopy (AFM) imaging of Aβ oligomers in membranes reveal heterogeneous channel morphologies. Previously, we modeled the channels in a non-tilted organization, parallel with the cross-membrane normal. Here, we modeled a β-barrel-like organization. β-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered β-sheet with antiparallel β-strands and a right-handed twist. Our explicit solvent molecular dynamics simulations of a range of channel sizes and polymorphic turns and comparisons of these with AFM image dimensions support a β-barrel channel organization. Different from the transmembrane β-barrels where the monomers are folded into a circular β-sheet with antiparallel β-strands stabilized by the connecting loops, these Aβ barrels consist of multimeric chains forming double β-sheets with parallel β-strands, where the strands of each monomer are connected by a turn. Although the Aβ barrels adopt the right-handed β-sheet twist, the barrels still break into heterogeneous, loosely attached subunits, in good agreement with AFM images and previous modeling. The subunits appear mobile, allowing unregulated, hence toxic, ion flux.

Reduced Lipid Bilayer Thickness Regulates the Aggregation and Cytotoxicity of Amyloid-β

“…Early A␤ oligomers may perform their toxic function through interactions with the neuronal lipid bilayer (4,5). Pore formation has been suggested to facilitate disruption of the ionic gradient across neuronal membranes (6,7). Alternatively, elongation of the amyloid species on the bilayer may remove lipids from the membrane and create holes that allow for the uncontrolled transit of biomacromolecules across the membrane (8,9).…”

Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates

“…Amyloid oligomers with distinct structural features exhibit different cytotoxicity. A diversity of structural models has been suggested for amyloid oligomers, including β-barrels (25)(26)(27)(28), α-helix bundles (29), and parallel in-register β-sheets (30). However, structural characterization of toxic amyloid oligomers at the atomic level is hindered by their highly transient and polymorphic properties.…”

Disruption of Calcium Homeostasis in Alzheimer’s Disease: Role of Channel Formation by β Amyloid Protein

“…Strodel et al proposed a model of AβP(1-42) pores which consist of tetrameric and hexameric β-sheet subunits from the observations in NMR (Strodel et al, 2010). The dimension, shape, and subunit organization of these models were in good agreement with the morphological observations using high resolution AFM that demonstrated that AβPs form pore-like structures on mica plates or on reconstituted membranes (Lal et al, 2007, Jang et al, 2010. Furthermore, the presence of pore-like structures of AßPs in vivo was demonstrated in the neuronal cell membrane of the brains of AD patients and of AD-model mice.…”