Abstract:The aggregation and deposition of amyloid β (Aβ) peptide onto neuronal cells, with consequent cellular membrane perturbation, are central to the pathogenesis of Alzheimer's disease (AD). Substantial evidence reveals that biological membranes play a key role in this process. Thus, elucidating the mechanisms by which Aβ interacts with biomembranes and becomes neurotoxic is fundamental to developing effective therapies for this devastating progressive disease. However, the structural basis behind such interaction… Show more
Aβ peptides form by processing of the β-amyloid precursor protein by β- and γ-secretases ( 4 , 146 ). The role of lipids in Aβ fibril formation has been characterized extensively ( 4 , 27 , 32 , 47 , 147 ), including the influence of membrane composition on fibril morphology ( 18 , 27 ). Aβ(1–42) is associated with diffuse plaques in the early stages of AD.…”
Section: Overview Of Amyloid Assemblymentioning
confidence: 99%
“…In many cases, nucleation is significantly accelerated in the presence of negatively charged lipids ( 41 , 45 , 46 ). In general, liposome models are able to replicate some of the features of fibrils found in vivo , but often the outcomes of experiments with liposomes are dependent on experimental details, such as whether a peptide is added to preformed liposomes or incorporated into the membranes during formation ( 18 , 27 , 47 , 48 ). The dependence of the outcome on both the method of preparation and the membrane composition makes comparisons between fibrils formed in vitro and those isolated from tissues more challenging.…”
Aβ peptides form by processing of the β-amyloid precursor protein by β- and γ-secretases ( 4 , 146 ). The role of lipids in Aβ fibril formation has been characterized extensively ( 4 , 27 , 32 , 47 , 147 ), including the influence of membrane composition on fibril morphology ( 18 , 27 ). Aβ(1–42) is associated with diffuse plaques in the early stages of AD.…”
Section: Overview Of Amyloid Assemblymentioning
confidence: 99%
“…In many cases, nucleation is significantly accelerated in the presence of negatively charged lipids ( 41 , 45 , 46 ). In general, liposome models are able to replicate some of the features of fibrils found in vivo , but often the outcomes of experiments with liposomes are dependent on experimental details, such as whether a peptide is added to preformed liposomes or incorporated into the membranes during formation ( 18 , 27 , 47 , 48 ). The dependence of the outcome on both the method of preparation and the membrane composition makes comparisons between fibrils formed in vitro and those isolated from tissues more challenging.…”
“…Liposomes are commonly used tools for the analysis of interactions between amyloids and lipid membranes. 19,20 We used the agarose embedded liposomes (blue, app. 100 μm in diameter, Figure S2 ) for long time imaging and the fluorescence tagged [II] peptides (KFFIIK with FITC (green) and EFFIIE with rhodamine B (red)) to identify their membrane interactions (Figure 1A) .…”
Aggregation of otherwise soluble proteins into amyloid structures is a hallmark of many disorders, such as Alzheimers and Parkinsons diseases. There is increasing evidence and acceptance that instead of ordered amyloid assemblies, the misfolded oligomer aggregations are the main toxic structures. However, there is no system to study the mechanism and kinetics of aggregation, distinguish between ordered structures and misfolded oligomers, and correlate the structures to their toxicity. The exact role of oligomer aggregation in the pathological process remains to be elucidated. Here, we use an engineered co-assembling oppositely charged amyloid-like peptide pair ([II]) to relate its aggregation to toxicity. The toxicity mechanism of [II] is through cell membrane damage and stress, as shown with YAP and eIF2a; biomarkers, as in the amyloid protein-initiated diseases. Albumin is used to control the aggregation of [II], and so its toxicity. This study represents a molecular engineering strategy to study the aggregation process of amyloid-like structures in diseases. Understanding the nature of protein aggregation through engineered peptides paves the way for future designs and drug development applications.
“…44,45 Previous work either proposed the disruption of membranes by peptides or the modulation of peptide self-assembly by membranes as the initial process in relation to disease, or considered both processes as concomitant. 33,35,36,46,47 Sparr and Linse emphasized the important role of membrane properties, and particularly the protein-to-lipid ratio, among the factors contributing to lipid-protein interactions in amyloid formation. 48…”
Section: Introductionmentioning
confidence: 99%
“…44,45 Previous work either proposed the disruption of membranes by peptides or the modulation of peptide self-assembly by membranes as the initial process in relation to disease, or considered both processes as concomitant. 33,35,36,46,47 Sparr and Linse emphasized the important role of membrane properties, and particularly the protein-to-lipid ratio, among the factors contributing to lipid-protein interactions in amyloid formation. 48 In this work, we focused our attention on the role of the oxidized membrane lipid PazePC on the structure and self-assembly kinetics of the amyloid β (1−40) peptide (Aβ40) 2,3,49 and the antimicrobial peptide uperin 3.5 (U3.5) (Figure 1b), aggregating near model membranes.…”
The self-assembly of peptides into supramolecular fibril structures has been linked to neurodegenerative diseases such as Alzheimer's disease but has also been observed in functional roles. Peptides are physiologically exposed to crowded environments of biomacromolecules, and particularly membrane lipids, within a cellular milieu. Previous research has shown that membranes can both accelerate and inhibit peptide self-assembly. Here, we studied the impact of biomimetic membranes that mimic cellular oxidative stress and compared this to mammalian and bacterial membranes. Using molecular dynamics simulations and experiments, we propose a model that explains how changes in peptide-membrane binding, electrostatics, and peptide secondary structure stabilization determine the nature of peptide self-assembly. We explored the influence of zwitterionic (POPC), anionic (POPG) and oxidized (PazePC) phospholipids, as well as cholesterol, and mixtures thereof, on the self-assembly kinetics of the amyloid β (1–40) peptide (Aβ40), linked to Alzheimer's disease, and the amyloid-forming antimicrobial peptide uperin 3.5 (U3.5). We show that the presence of an oxidized lipid had similar effects on peptide self-assembly as the bacterial mimetic membrane. While Aβ40 fibril formation was accelerated, U3.5 aggregation was inhibited by the same lipids at the same peptide-to-lipid ratio. We attribute these findings and peptide-specific effects to differences in peptide-membrane adsorption with U3.5 being more strongly bound to the membrane surface and stabilized in an α-helical conformation compared to Aβ40. Different peptide-to-lipid ratios resulted in different effects. Molecular dynamics simulations provided detailed mechanistic insights into the peptide-lipid interactions and secondary structure stability. We found that electrostatic interactions are a primary driving force for peptide-membrane interaction, enabling us to propose a model for predictions how cellular changes might impact peptide self-assembly in vivo, and potentially impact related diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
