Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity

Abstract

The amyloid cascade hypothesis states that senile plaques, composed of amyloid β (Aβ) fibrils, play a key role in Alzheimer's disease (AD). However, recent experiments have shown that Aβ oligomers are more toxic to neurons than highly ordered fibrils. The molecular mechanism underlying this observation remains largely unknown. One of the possible scenarios for neurotoxicity is that Aβ peptides create pores in the lipid membrane that allow Ca²⁺ ions to enter cells, resulting in a signal of cell apoptosis. Hence, one might think that oligomers are more toxic due to their higher ability to create ion channels than fibrils. In this work, we study the effect of Aβ42 dodecamer and fibrils on a neuronal membrane, which is similar to that observed in AD patients, using all-atom molecular dynamics simulations. Due to short simulation times, we cannot observe the formation of pores, but useful insight on the early events of this process has been obtained. Namely, we showed that dodecamer distorts the lipid membrane to a greater extent than fibrils, which may indicate that ion channels can be more easily formed in the presence of oligomers. Based on this result, we anticipate that oligomers are more toxic than mature fibrils, as observed experimentally. Moreover, the Aβ-membrane interaction was found to be governed by the repulsive electrostatic interaction between Aβ and the ganglioside GM1 lipid. We calculated the bending and compressibility modulus of the membrane in the absence of Aβ and obtained good agreement with the experiment. We predict that the dodecamer will increase the compressibility modulus but has little effect on the bending modulus. Due to the weak interaction with the membrane, fibrils insignificantly change the membrane elastic properties.

Figure 1

(A) Initial structure of the Aβ42 dodecamer obtained from the three tetramers using the docking method. (B) Mature fibril structure obtained by duplicating the PDB 2NAO structure, which consists of six chains. (C) Structure of a dodecamer obtained from the 500 ns MD run in solution. (D) As in C but for a mature fibril. The N-terminal and C-terminal atoms are shown with cyan and orange balls, respectively.

Figure 2

(A) Lipid molecules in the membrane (view in direction perpendicular to the membrane surface), DPPC—blue, POPC—orange, CHL1—red, PSM—green, and GM1—purple. (B) The z-axis is perpendicular to the surface of the membrane and z = 0 at the center of the membrane. (C) Typical initial conformation of the membrane–dodecamer complex, water, and ion molecules are removed for clarity. The P atoms of lipids are shown as purple balls, and the N-terminal and C-terminal atoms of the Aβ peptide are show as cyan and orange balls, respectively. (D) As in C but for the membrane–fibril complex. The Aβ structure shown in (C,D) was obtained from the 500 ns simulation in solution.

Figure 3

Minimum distance between Aβ and the center of the membrane along the z-axis as a function of time. The dashed line represents the membrane surface.

Figure 4

Electrostatic potential on the surface of dodecamer, fibril, and membrane. The color bar from red to blue indicates from negative to positive potential, respectively.

Figure 5

(Left) The GM1 molecules are composed of neuraminic acid, ceramide, and sugar. (Right) GM1 molecule in a membrane–solution system, water molecules are shown in transparent cyan, other lipids in yellow, and spheres refer to ions.

Figure 6

Distribution of lipids. The results were obtained by averaging over all trajectories for the membrane–dodecamer and membrane–fibril complexes.

Figure 7

Radial distribution function g(r) of cholesterol molecules in membrane–dodecamer and membrane–fibril systems. The Aβ-free case is shown in orange. The reference point is the center of mass of cholesterol residues.

Figure 8

Tail order parameters of lipid molecules in the absence and presence of Aβ. Results were averaged over 10 MD trajectories.

Figure 9

Distribution of the membrane thickness for the membrane alone, membrane–dodecamer, and membrane–fibril complexes. The results were averaged over all MD trajectories.

Figure 10

Distribution of the depth of cracks on the membrane surface for the membrane alone, membrane–dodecamer, and membrane–fibril complexes. The results were averaged over all MD trajectories.

Figure 11

Position of the deepest crack observed in the dodecamer simulation (top). This crack spans almost half of the membrane thickness (bottom).