Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer's disease

Abstract

The association of the amyloid-β (Aβ) peptide with cellular membranes is hypothesized to be the underlying phenomenon of neurotoxicity in Alzheimer's disease. Misfolding of proteins and peptides, as is the case with Aβ, follows a progression from a monomeric state, through intermediates, ending at long, unbranched amyloid fibers. This tutorial review offers a perspective on the association of toxic Aβ structures with membranes as well as details of membrane-associated mechanisms of toxicity.

Fig. 1. The amyloid hypothesis for Alzheimer’s disease

The aggregation of amyloid-β is highly diverse and poorly understood. Mounting evidence points to oligomers as being the most toxic agent in Alzheimer’s disease; however, intermediate structures are transient and heterogeneous. Additionally, the mechanism by which Aβ can be neurotoxic has not been fully elucidated. One prevailing hypothesis suggests that Aβ can be toxic through a membrane disruption mechanism.

Fig. 2. Various structures of Aβ in solution and detergents characterized by NMR

(a) Aβ_1–40 as a partially folded structure in the presence of 50 mM NaCl, with residues 13 to 23 forming a 3₁₀ helix. (b) Solution NMR structure of 0.05% SDS-stabilized pre-globulomer of Aβ_1–42 (top) compared with the basic fold of the fibrils of Aβ_1–42 (bottom). Adapted with permission from Yu et al. Copyright 2009 American Chemical Society. (c) Structural schematic of β-balls formed at low pH in the absence (top) and presence (bottom) of DSS. These structures both show a pinwheel, or micelle-like, arrangement of monomers. Reprinted with permission from Laurents et al. 2005. Copyright 2005 Journal of Biological Chemistry.

Fig. 3. Model of GM1 ganglioside-clusters leading to the formation of toxic Aβ species

Studies have found that low Aβ:GM1 ratios yield an α-helical Aβ structure, while an increasing Aβ:GM1 ratio produces fibrils. Reprinted with permission from Ikeda et al. 2011. Copyright 2011 American Chemical Society.

Fig. 4. A two-step mechanism of membrane disruption

Upon addition of Aβ to a membrane solution (a), it is capable of binding to the membrane and forming ion channel-like pores (b). Appearance of Aβ pores is increased by the presence of gangliosides in the membrane composition. Furthermore, gangliosides mediate a second step of membrane disruption, a fiber-dependent step, which acts via a detergent-like mechanism to fragment the lipid bilayer (c).