Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Abstract

Self-assembly of amyloid-β (Aβ) peptides in nonequilibrium, flowing conditions is associated with pathogenesis of Alzheimer’s disease. We examined the role of biologically relevant, nonequilibrium, flowing conditions in the desorption, diffusion, and integration of Aβ-lipid assemblies at the membrane surface using a microchannel connected with microsyringes. A 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer was formed on a glass substrate and incubated in Aβ solution under either a quiescent condition (no flow) or flowing condition for 24 h. Although dot-like aggregates (<1 μm) comprising Aβ fibrils formed on the DMPC membrane under the quiescent condition, larger plaque-like aggregates formed under the flowing condition, suggesting that nonequilibrium continuous flow governs the cytotoxicity of Aβ species. We propose that Aβ adsorption on the membrane surface involves spontaneous desorption of Aβ-lipid to form self-assembling aggregates, with this accelerated by surface shear forces. These findings suggest that nonequilibrium, flowing conditions influence inter/intra-molecular Aβ-fibril formation to trigger formation of amyloid plaques.

The association of lipids with amyloid fibrils

“…A recent study of Aβ fibril formation in flow conditions concluded that early forming fibrils and membranes form an equilibrium between the membrane-bound peptide and peptide–lipid aggregates in solution. This process implicitly favors the incorporation of lipids into fibrils at an early stage of fibril formation ( 143 ). This stage of the process is where the most toxic membrane-active species form and corresponds to the formation of compact structures in AD ( Fig.…”

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

“…While shear-induced monomeric protein dynamics were explored by experimental , and computational − studies, and lipid systems were also investigated under shear flows, − we still lack an atomic description of Aβ aggregates under fluid flows in the bulk solution and at the surface of membranes. Yet is it known that flowing acting on the membrane surface showed desorption, diffusion and collision of Aβ-lipid aggregates forming larger plaque-like aggregates . Overall, hydrodynamic flow fields in ISS are likely to change the conformational ensemble states assessed by small Aβ oligomers and may promote very rare excited oligomers …”

“…More elaborated microfluidic experiments could also approach in vivo conditions. 120,125,142 These combined studies could help design more efficient drugs targeting Aβ monomer and oligomers. 135,143…”

“…Finally, coarse-grained simulations, taking into account the nonregular and tortuous geometry and the alterations of the ISS space, crowding including prion protein and NMDA receptor, and fluid flow variations during the sleep–wake cycle could unveil unexpected phenomena and aggregates. More elaborated microfluidic experiments could also approach in vivo conditions. ,, These combined studies could help design more efficient drugs targeting Aβ monomer and oligomers. , …”

“…Yet is it known that flowing acting on the membrane surface showed desorption, diffusion and collision of Aβ-lipid aggregates forming larger plaque-like aggregates. 125 Overall, hydrodynamic flow fields in ISS are likely to change the conformational ensemble states assessed by small Aβ oligomers and may promote very rare excited oligomers. 126…”