A Mechanistic Understanding of Self-Propagating Amyloid-β Oligomer Conformations in Alzheimer Disease

Alzheimer disease (AD) is a fatal neurodegenerative disorder characterized by the widespread deposition of proteinaceous plaques abundant in amyloid-β (Aβ) aggregates. Although the plaques mainly contain high molecular weight, insoluble Aβ fibrils, the low molecular weight soluble aggregates called oligomers have been shown as the primary toxic species responsible for synaptic dysfunction and neuronal loss in AD. The process of aggregation is nucleation-dependent, but also highly stochastic and inhomogeneous resulting in biophysically diverse assemblies. Recent advances in the field indicate a potential correlation between the phenotypic diversity observed in AD subtypes and aggregate polymorphism. Therefore, understanding the molecular mechanisms which lead to the generation of diverse Aβ oligomer structures (strains), and their subsequent propagation to polymorphic fibrils is crucial in establishing structure-phenotype correlations in AD. Our laboratory has previously characterized a specific Aβ oligomer called large fatty acid-derived oligomers (LFAOs), generated in the presence of fatty acid micelles. The work presented here has two main objectives: i) to determine the biophysical and biochemical properties of LFAOs in the context of strain behavior, particularly in the propagation of their structure; and ii) to determine the mechanism of oligomer strain generation by a family of lipids that are known to interact with Aβ. This work details the mechanism of LFAO strain propagation, which occurs in three distinctive phases involving a key intermediate. Also detailed is how LFAOs affect neuronal cells and selectively induce cerebral amyloid angiopathy (CAA) in transgenic AD mice brains, cementing the idea that distinct oligomer strains can influence AD phenotypes. Lastly, this work reveals that a family of Aβ oligomer strains can be generated in interfacial conditions, suggesting that lipids present in the AD brain may play a role in strain generation. Overall, this brings forth fundamental mechanistic paradigms involved in oligomer strain generation and propagation that has invoked substantial insights into AD pathology

An Experimental Study of Applied Ground Loads in Landing

Results are presented of an experimental investigation made of the applied ground loads and the coefficient of friction between the tire and the ground during the wheel spin-up process in impacts of a small landing gear under controlled conditions on a concrete landing strip in the Langley impact basin. The basic investigation included three major phases: impacts with forward speed at horizontal velocities up to approximately 86 feet per second, impacts with forward speed and reverse wheel rotation to simulate horizontal velocities up to about 273 feet per second, and spin-up drop tests for comparison with the other tests. In addition to the basic investigation, supplementary tests were made to evaluate the drag-load alleviating effects of prerotating the wheel before impact so as to reduce the relative velocity between the tire and ground. In the presentation of the results, an attempt has been made to interpret the experimental data so as to obtain some insight into the physical phenomena involved in the wheel spin-up process

Fatty Acid Concentration and Phase Transitions Modulate Aβ Aggregation Pathways

Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aβ homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aβ and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Aβ dynamics distinctively in three broadly-defined FAconcentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Aβ, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aβ aggregation pathways

NACA Research Memorandums

Report presenting information on landing gear applied drag loads and the nature of wheel spin-up in landing based on testing in the Langley impact basin. Particular attention is paid to the nature and variation of the coefficient of friction between the tire and runway during the wheel spin-up process. Results regarding the fundamentals of the process, comparison of maximum loads, variation of coefficient of friction, and effect of prerotation are provided

Large Fatty Acid-Derived Aβ42 Oligomers Form Ring-Like Assemblies

As the primary toxic species in the etiology of Alzheimer disease (AD) are low molecular weight oligomers of Aβ, it is crucial to understand the structure of Aβ oligomers for gaining molecular insights into AD pathology. We have earlier demonstrated that in the presence of fatty acids, Aβ42 peptides assemble as 12-24mer oligomers. These Large Fatty Acid-derived Oligomers (LFAOs) exist predominantly as 12mers at low and as 24mers at high concentrations. The 12mers are more neurotoxic than the 24mers and undergo self-replication, while the latter propagate to morphologically distinct fibrils with succinct pathological consequences. In order to glean into their functional differences and similarities, we have determined their structures in greater detail by combining molecular dynamic simulations with biophysical measurements. We conjecture that the LFAO are made of Aβ units in an S-shaped conformation, with the 12mers forming a double-layered hexamer ring (6 × 2) while the structure of 24mers is a double-layered dodecamer ring (12 × 2). A closer inspection of the (6 × 2) and (12 × 2) structures reveals a concentration and pH dependent molecular reorganization in the assembly of 12 to 24mers, which seems to be the underlying mechanism for the observed biophysical and cellular properties of LFAOs

Biophysical Characteristics of Lipid-Induced Aβ Oligomers Correlate to Distinctive Phenotypes In Transgenic Mice

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder that affects cognition and memory. Recent advances have helped identify many clinical sub-types in AD. Mounting evidence point toward structural polymorphism among fibrillar aggregates of amyloid-β (Aβ) to being responsible for the phenotypes and clinical manifestations. In the emerging paradigm of polymorphism and prion-like propagation of aggregates in AD, the role of low molecular weight soluble oligomers, which are long known to be the primary toxic agents, in effecting phenotypes remains inconspicuous. In this study, we present the characterization of three soluble oligomers of Aβ42, namely 14LPOs, 16LPOs, and GM1Os with discreet biophysical and biochemical properties generated using lysophosphatidyl glycerols and GM1 gangliosides. The results indicate that the oligomers share some biophysical similarities but display distinctive differences with GM1Os. Unlike the other two, GM1Os were observed to be complexed with the lipid upon isolation. It also differs mainly in detection by conformation-sensitive dyes and conformation-specific antibodies, temperature and enzymatic stability, and in the ability to propagate morphologically-distinct fibrils. GM1Os also show distinguishable biochemical behavior with pronounced neuronal toxicity. Furthermore, all the oligomers induce cerebral amyloid angiopathy (CAA) and plaque burden in transgenic AD mice, which seems to be a consistent feature among all lipid-derived oligomers, but 16LPOs and GM1Os displayed significantly higher effect than the others. These results establish a correlation between molecular features of Aβ42 oligomers and their distinguishable effects in transgenic AD mice attuned by lipid characteristics, and therefore help bridge the knowledge gap in understanding how oligomer conformers could elicit AD phenotypes

Cattle facilities

Published November 1980. Facts and recommendations in this publication may no longer be valid. Please look for up-to-date information in the OSU Extension Catalog: http://extension.oregonstate.edu/catalo