Size-Dependent Interaction of Amyloid β Oligomers with Brain Total Lipid Extract Bilayer—Fibrillation Versus Membrane Destruction

Abstract

Amyloid β, Aβ(1–42), is a component of senile plaques present in the brain of Alzheimer’s disease patients and one of the main suspects responsible for pathological consequences of the disease. Herein, we directly visualize the Aβ activity toward a brain-like model membrane and demonstrate that this activity strongly depends on the Aβ oligomer size. PeakForce quantitative nanomechanical mapping mode of atomic force microscopy imaging revealed that the interaction of large-size (LS) Aβ oligomers, corresponding to high-molecular-weight Aβ oligomers, with the brain total lipid extract (BTLE) membrane resulted in accelerated Aβ fibrillogenesis on the membrane surface. Importantly, the fibrillogenesis did not affect integrity of the membrane. In contrast, small-size (SS) Aβ oligomers, corresponding to low-molecular-weight Aβ oligomers, created pores and then disintegrated the BTLE membrane. Both forms of the Aβ oligomers changed nanomechanical properties of the membrane by decreasing its Young’s modulus by ∼45%. Our results demonstrated that both forms of Aβ oligomers induce the neurotoxic effect on the brain cells but their action toward the membrane differs significantly.

Alzheimer's disease-related amyloid β peptide causes structural disordering of lipids and changes the electric properties of a floating bilayer lipid membrane

“…37 However, all simulations concerning homogeneous and heterogeneous defects distribution were made for membranes containing pores of the same radius. 37 Our AFM data 16 showed that Ab generated pores of different sizes in the lipid bilayers. To examine whether the change in the pore radius affects the position of the phase angle vs. frequency minimum or not, the EIS spectra for the membrane containing pores of different radii were simulated (Fig.…”

“…17,18 The results of our previous AFM study lacked information about the changes inside the membrane. 16 Therefore, the goal of the present research is to study the AbO-induced changes in the oating bilayer lipid membrane (fBLM) using polarizationmodulation infrared reection-absorption spectroscopy (PM-IRRAS) and different electrochemical techniques. These techniques have been successfully applied to study the effect of antimicrobial peptides on the fBLM properties.…”

The Membrane Axis of Alzheimer's Nanomedicine

“…In contrast, the aggregation of large‐sized Aβ oligomers was accelerated on the BTLE membrane surface without affecting the membrane integrity. [ 72 ] Small‐sized Aβ oligomers and globular nonfibrillar oligomers have been considered as the more toxic species in causing neurodegeneration. [ 73 ] Alternatively, Aβ could induce channel‐like perforation in neuronal cell membranes (Figure 2), causing an increase in membrane conductance as well as intracellular calcium and ethidium bromide influxes in a concentration‐ and time‐dependent manner.…”

“…Moreover, recent studies have revealed that this detergent-like activity of the peptide strongly depends on the structure and size of the Aβ oligomers. [63,72] For example, globular nonfibrillar oligomers caused the largest reduction of lipid diffraction in anionic 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) lipid monolayers upon insertion, compared with short fibrillar oligomers and monomers. [63] Small-sized Aβ oligomers, corresponding to low molecular-weight Aβ oligomers, could destroy the brain total lipid extract (BTLE) membrane bilayer by lipid extraction.…”

Understanding and exploiting interactions between cellular proteostasis pathways and infectious prion proteins for therapeutic benefit

“…Although the role of oligomers in disease progression is clear, the specific mechanisms by which they exert toxicity is still debatable. Due to their increased hydrophobicity, misfolded protein oligomers are thought to bind and stabilize within the cellular lipid bilayer, forming pores [114][115][116][117][118]. Other reports suggest that toxic oligomers bind specific extracellular receptors that will trigger deleterious cascades leading to cell death [80,81].…”