Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

Abstract

The assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid β (Aβ) proteins is considered as a major cause for the development of Alzheimer's disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that Aβ42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein. As a result, the misfolded Aβ42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.Self-assembly is a widely spread phenomenon in biology and the assembly of proteins into nanoaggerates with various morphologies is a phenomenon of a special attention for decades. Evidence strongly suggests that the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is due to the self-assembly of amyloid β (Aβ) and α-synuclein oligomers, respectively 1 . These oligomers appear to disrupt the cell homeostasis, by various mechanisms, resulting in the early stages of neurodegenerative diseases 2-4 . The amyloid cascade hypothesis (ACH) 5 is the major model that describes the pathology of AD and other neurodegenerative diseases 5-9 . However, several orders higher concentrations of Aβ compared with that found in vivo are required for the spontaneous aggregation of Aβ, which challenges the validity of ACH. We have discovered that amyloid proteins and peptides are capable of assembling into aggregates at nanomolar concentration range if the process occurs at the surface-liquid interface 10,11 . In the present study, we monitored the aggregation of Aβ42 at its physiologically relevant low concentration (10 nM) on supported lipid bilayers (SLBs) formed by 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-snglycero-3-phospho-L-serine (POPS).Direct time-lapse AFM imaging revealed Aβ42 aggregation on the bilayer surfaces, while no self-assembly of Aβ42 was detected in bulk solution. We performed computational modeling of the aggregation process on the membrane surfaces to demonstrate that interaction of Aβ42 dramatically changes the conformation of Aβ42 monomers. Moreover, membrane-bound Aβ42 proteins trigger the assembly of dimers, trimers, and tetramers, propagating the misfolded states of the Aβ42 molecules. Thus, interaction with membranes results in the transition of Aβ42 into the aggregation-prone, misfolded conformations. Such conformations have not been reported in

Interaction of Amyloidogenic Proteins with Membranes and Molecular Mechanism for the Development of Alzheimer’s disease

“…This A conformation with higher -content rapidly forms a dimer with a free monomer. Similar interaction between A and lipid bilayer has been observed to induce trimer and tetramer formation [26]. A peptides are produced by proteolytic cleavage of membrane protein APP.…”

“…The membrane damage by the oligomers is considered as one of the major neurotoxic mechanism associated with the disease development. The recent findings on the membrane catalysis of amyloid aggregation highlight another important property of membranes in the development of the diseases [26]. According to the model shown in (Figure 1), self-assembly of the disease-prone amyloid aggregates is initiated and driven by the interaction of amyloid proteins with the cellular membrane.…”

“…The interaction of A with the lipid membrane is considered to have a two-way effect toward the disease development: (i) it changes the protein conformation in such a way that the changed A structure triggers the oligomer formation, and (ii) the formed oligomers can alter the membrane structure to initiate the toxicity (Figure 1). Molecular dynamics simulations show that the transient interaction of A with POPC has an extensive effect towards generating -structure in the protein, which has never been seen in solution [26]. The -content increases up to 17% as the peptide transiently interacts with the POPC bilayer.…”

“…In all cases, aggregates have been observed to be mainly oligomers, no fibrils have been detected. The presence of 150 mM NaCl further increases the on-membrane aggregation [26]. Lipid vesicles have also been used to probe the aggregation kinetics of A, and the acceleration of the aggregation has been observed [27].…”