Nanoscale assembly of amyloid oligomers at physiologically relevant conditions

University Of Nebraska Medical Center, Omaha NE

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Abstract

According to numerous in vitro studies, formation of amyloid beta (Ab) and other amyloidogenic protein is a self-assembly process that results in the production of neurotoxic oligomeric aggregates along with fibrillar structures, a hallmark of diseases such as Alzheimer’s disease. However, the vast majority of in vitro studies are performed at Ab concentrations of several orders higher than the physiologically relevant concentrations of Aβ in the brain; no aggregation of Aβ is observed at the low nanomolar concentration found in vivo. This suggests that the assembly of Aβ in aggregates in vivo utilizes pathways different from those used in experiments in vitro. We discovered that spontaneous assembly of Aβ42 oligomers from monomers within the physiologically relevant concentration range can occur by utilizing the on-surface aggregation mechanism. Here, the surface acts as a catalyst for the aggregation process. We developed a model that explains the surface catalytic effect of the amyloid aggregation from monomers at low nanomolar concentrations. Our central hypothesis is that the self-assembly of Aβ oligomers is initiated by the interaction of amyloid proteins with the cellular membrane. The membrane effectively catalyzes amyloid aggregation by stabilizing aggregation-prone conformations of amyloids. A thorough testing of this hypothesis is the major goal of this application. The rationale for the proposed goal is that understanding the fundamental mechanisms of membrane-mediated aggregation will guide the development of practical approaches to control the aggregation process. The objective of this proposal is to characterize the on-surface formation of Aβ oligomers, identify the aggregation-prone composition of cellular membranes, and develop a molecular model for future use in translational studies. Guided by strong preliminary data, we will test our central hypothesis through the following three specific aims: Aim 1: Characterize the aggregation process of Ab monomers catalyzed by cellular membranes with different lipid compositions. Aim 2: Evaluate contributions of free lipids of cell membranes into the membrane catalysis of amyloid aggregation. Aim 3: Develop a molecular model for the membrane catalysis phenomenon using theoretical and computational approaches. Aim 1 is focused on testing our hypothesis that the lipid composition of the membrane bilayer is the defining factor in spontaneous aggregation of Ab proteins at physiological concentrations. Under Aim 2, we will test the hypothesis that free lipids contribute further to the membrane catalysis of amyloid aggregation. Aim 3 proposes the use of theoretical approaches and high-power computer modeling to gain structural insights into the molecular mechanism behind catalysis of aggregation by the cellular membrane. The predictions of the theory will be tested under Aims 1 and 2, and the experimental results obtained from these Aims will be further used to tune the theoretical methods. The proposed research plan, combining experimental studies with extensive computational modeling, will provide a molecular model for the aggregation process catalyzed by membranes at physiological concentrations of monomers. The development of potential preventions for the interaction of monomeric amyloids with membrane can help to control the aggregation process. This is a paradigm shift, which opens prospects for the development of efficient treatments, early diagnostics, and preventive therapies for Alzheimer's disease.