Aβ-membrane Interactions Research Articles

Understanding Aβ Peptide Binding to Lipid Membranes: A Biophysical Perspective.

Aβ peptides are known to bind neural plasma membranes in a process leading to the deposit of Aβ-enriched plaques. These extracellular structures are characteristic of Alzheimer's disease, the major cause of late-age dementia. The mechanisms of Aβ plaque formation and deposition are far from being understood. A vast number of studies in the literature describe the efforts to analyze those mechanisms using a variety of tools. The present review focuses on biophysical studies mostly carried out with model membranes or with computational tools. This review starts by describing basic physical aspects of lipid phases and commonly used model membranes (monolayers and bilayers). This is followed by a discussion of the biophysical techniques applied to these systems, mainly but not exclusively Langmuir monolayers, isothermal calorimetry, density-gradient ultracentrifugation, and molecular dynamics. The Methodological Section is followed by the core of the review, which includes a summary of important results obtained with each technique. The last section is devoted to an overall reflection and an effort to understand Aβ-bilayer binding. Concepts such as Aβ peptide membrane binding, adsorption, and insertion are defined and differentiated. The roles of membrane lipid order, nanodomain formation, and electrostatic forces in Aβ-membrane interaction are separately identified and discussed.

The structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels

Amyloid β (Aβ) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer’s disease. The relative roles of various Aβ isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy to characterize channel activities of four most prevalent Aβ peptides, Aβ1-42, Aβ1-40, and their pyroglutamylated forms (AβpE3-42, AβpE3-40) and correlate them with the peptides’ structural features. Solvent-induced fluorescence splitting of tyrosine-10 is discovered and used to assess the sequestration from the solvent and membrane insertion. Aβ1-42 effectively embeds in lipid membranes, contains large fraction of β-sheet in a β-barrel-like structure, forms multi-subunit pores in membranes, and displays well-defined ion channel features. In contrast, the other peptides are partially solvent-exposed, contain minimal β-sheet structure, form less-ordered assemblies, and produce irregular ionic currents. These findings illuminate the structural basis of Aβ neurotoxicity through membrane permeabilization and may help develop therapies that target Aβ-membrane interactions.

In-cell 31P solid-state NMR measurements of the lipid dynamics and influence of exogeneous β-amyloid peptides on live neuroblastoma neuro-2a cells

Non-specific disruption of cellular membranes induced by aggregation of exogeneous β-amyloid (Aβ) peptides is considered a viable pathological mechanism in Alzheimer's disease (AD). The solid-state nuclear magnetic resonance (ssNMR) spectroscopy has been widely applied in model liposomes to provide important insights on the molecular interactions between membranes and Aβ aggregates. Yet, the feasibility of in-cell ssNMR spectroscopy to probe Aβ-membrane interactions in native cellular environments has rarely been tested. Here we report the application of in-cell31P ssNMR spectroscopy on live mouse neuroblastoma Neuro-2a (N2a) cells under moderate magic angle spinning (MAS) conditions. Both cell viability and cytoplasmic membrane integrity are retained for up to six hours under 5 kHz MAS frequency at 277 K, which allow applications of direct-polarization 31P spectroscopy and 31P spin-spin (T2) relaxation measurements. The 31P T2 relaxation time constant of N2a cells is significantly increased compared with the model liposome prepared with comparable major phospholipid compositions. With the addition of 5 μM 40-residue Aβ (Aβ1–40) peptides, the 31P T2 relaxation is instantly accelerated. This work demonstrates the feasibility of using in-cell31P ssNMR to investigate the Aβ-membrane interactions in the biologically relevant cellular system.

Concentration-Dependent Effects of Cholesterol on the Dimerization of Amyloid-β Peptides in Lipid Bilayers.

Membrane disruption mediated by the accumulation of amyloid-β (Aβ) on cell membranes is central to the pathogenesis of Alzheimer's disease (AD). Cholesterol, an important component of membranes, is well-recognized as a risk factor in AD. It can affect the aggregation and pore formation of Aβ on membranes whereas the specific effects are rather complex, particularly regarding the non-linear response to cholesterol concentrations. Yet, the mechanistic understanding of the role of cholesterol in Aβ-membrane interactions remains incomplete. Herein, we employed microsecond-scale molecular dynamics simulations to investigate the effects of cholesterol on Aβ dimerization in a lipid bilayer containing different molar ratios of cholesterol (0, 20, and 40 mol %). Cholesterol reduces the time required for the formation of stable dimers and exerts dual effects on Aβ-membrane interactions. First, cholesterol promotes the extraction of the C-terminal region from the membrane to water. Consequently, at the ratios of 0 and 20 mol %, peptides are anchored at the membrane-water interface, but they are repelled to water at a ratio of 40 mol % with high structural flexibility. Second, cholesterol weakens Aβ-membrane interactions, thereby enhancing inter-peptide interactions. The former is favorable for dimerization while the latter is not. The balance between two factors eventually leads to a non-monotonic effect on the degree of dimerization, whereby the number of inter-peptide contacts is the largest at a cholesterol ratio of 20 mol %. These results provide atomistic insights into the regulation mechanism of Aβ42 aggregation by cholesterol and help to understand the pathological link between cholesterol and AD.

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity.

The amyloid cascade hypothesis states that senile plaques, composed of amyloid β (Aβ) fibrils, play a key role in Alzheimer’s disease (AD). However, recent experiments have shown that Aβ oligomers are more toxic to neurons than highly ordered fibrils. The molecular mechanism underlying this observation remains largely unknown. One of the possible scenarios for neurotoxicity is that Aβ peptides create pores in the lipid membrane that allow Ca2+ ions to enter cells, resulting in a signal of cell apoptosis. Hence, one might think that oligomers are more toxic due to their higher ability to create ion channels than fibrils. In this work, we study the effect of Aβ42 dodecamer and fibrils on a neuronal membrane, which is similar to that observed in AD patients, using all-atom molecular dynamics simulations. Due to short simulation times, we cannot observe the formation of pores, but useful insight on the early events of this process has been obtained. Namely, we showed that dodecamer distorts the lipid membrane to a greater extent than fibrils, which may indicate that ion channels can be more easily formed in the presence of oligomers. Based on this result, we anticipate that oligomers are more toxic than mature fibrils, as observed experimentally. Moreover, the Aβ–membrane interaction was found to be governed by the repulsive electrostatic interaction between Aβ and the ganglioside GM1 lipid. We calculated the bending and compressibility modulus of the membrane in the absence of Aβ and obtained good agreement with the experiment. We predict that the dodecamer will increase the compressibility modulus but has little effect on the bending modulus. Due to the weak interaction with the membrane, fibrils insignificantly change the membrane elastic properties.

Free Cholesterol Accelerates Aβ Self-Assembly on Membranes at Physiological Concentration.

The effects of membranes on the early-stage aggregation of amyloid β (Aβ) have come to light as potential mechanisms by which neurotoxic species are formed in Alzheimer’s disease. We have shown that direct Aβ-membrane interactions dramatically enhance the Aβ aggregation, allowing for oligomer assembly at physiologically low concentrations of the monomer. Membrane composition is also a crucial factor in this process. Our results showed that apart from phospholipids composition, cholesterol in membranes significantly enhances the aggregation kinetics. It has been reported that free cholesterol is present in plaques. Here we report that free cholesterol, along with its presence inside the membrane, further accelerate the aggregation process by producing aggregates more rapidly and of significantly larger sizes. These aggregates, which are formed on the lipid bilayer, are able to dissociate from the surface and accumulate in the bulk solution; the presence of free cholesterol accelerates this dissociation as well. All-atom molecular dynamics simulations show that cholesterol binds Aβ monomers and significantly changes the conformational sampling of Aβ monomer; more than doubling the fraction of low-energy conformations compared to those in the absence of cholesterol, which can contribute to the aggregation process. The results indicate that Aβ-lipid interaction is an important factor in the disease prone amyloid assembly process.

Lipid membranes induce structural conversion from amyloid oligomers to fibrils

Formation of amyloid oligomers and fibrils underlies the pathogenesis of a number of neurodegenerative diseases such as Alzheimer’s. One mechanism of action by which Aβ aggregates cause neuronal toxicity is through interactions with cellular membranes. Aβ aggregates have been shown to disrupt membrane integrity via pore formation, membrane thinning, or lipid extraction. At the same time, lipid membranes also affect the rate of Aβ aggregation and remodel pre-formed Aβ fibrils. Here we show that Aβ42 globulomers, a type of well-characterized and stable Aβ oligomers, convert to amyloid fibrils in the presence of DOPC liposomes. Electron paramagnetic resonance studies show that the fibrils converted from Aβ42 globulomers adopt the same structure as fibrils formed directly from monomers. Our results suggest that the interactions between Aβ oligomers and cellular membranes are dynamic. By converting Aβ oligomers to fibrils, the lipid membrane can reduce the membrane-disrupting activities caused by these oligomers. Modulation of Aβ-membrane interactions as a therapeutic strategy should take into account the dynamic nature of these interactions.

Conformation-specific perturbation of membrane dynamics by structurally distinct oligomers of Alzheimer's amyloid-β peptide.

The accumulation of toxic soluble oligomers of the amyloid-β peptide (Aβ) is a key step in the pathogenesis of Alzheimer's disease. There are mainly two conformationally distinct oligomers, namely, prefibrillar and fibrillar oligomers, that are recognized by conformation-specific antibodies, anti-amyloid oligomer antibody (A11) and anti-amyloid fibrillar antibody (OC), respectively. Previous studies have shown that the interaction of Aβ oligomers with the lipid membrane is one of the key mechanisms of toxicity produced by Aβ oligomers. However, the mechanism by which structurally distinct Aβ oligomers interact with the lipid membrane remains elusive. In this work, we dissect the molecular mechanism underlying the interaction of structurally distinct Aβ42 oligomers with the lipid membrane derived from the brain total lipid extract. Using picosecond time-resolved fluorescence spectroscopy, we show that the A11-positive Aβ42 oligomers undergo a membrane-induced conformational change that promotes the deeper immersion of these oligomers into the lipid hydrocarbon region and results in an increase in the membrane micro-viscosity. In sharp contrast, OC-positive Aβ42 oligomers interact with the lipid membrane via electrostatic interactions between the negatively-charged lipid headgroup and positively-charged residues of Aβ42 without perturbing the membrane dynamics. We show that the two structurally distinct Aβ42 oligomers demonstrating different interaction mechanisms with the lipid membrane eventually lead to the formation of typical amyloid fibrils. Our findings provide the mechanistic underpinning of the perturbation of lipid membranes by two conformationally distinct Aβ42 oligomers and can be of prime importance in designing anti-Alzheimer's therapeutic agents targeting Aβ-membrane interactions.

Ginsenoside Rb1 protected PC12 cells from Aβ25-35-induced cytotoxicity via PPARγ activation and cholesterol reduction

Accumulating evidences suggest that amyloid β (Aβ)-peptide plays a key role in pathogenesis of Alzheimer's disease (AD) through aggregation and deposition into plaques in neuronal cells. Membrane components such as cholesterol and gangliosides not only enhance the production of amyloidogenic Aβ fragments, but also appear to strengthen Aβ–membrane interaction. Ginsenoside Rb1 (GRb1) is a major active component of Panax, which is widely used to improve learning and memory. In the present study, whether ginsenoside Rb1 could protect pheochromocytoma cells (PC12 cells) from Aβ25-35-induced cytotoxicity including inhibiting cell growth, inducing apoptosis, producing reactive oxygen species (ROS), destroying the cytoskeleton and bringing about membrane toxicity was investigated. Our results indicated that ginsenoside Rb1 could serve as an agonist of peroxisom proliferator-activated receptor-γ (PPARγ) and reduce the level of cholesterol in AD model cells. Reduction of the Aβ25-35-induced cytotoxicity by lowering cholesterol was evidenced by reduction of ROS production, lipid peroxidation, and protection of cytoskeleton and membrane surface rigidity. Most importantly, the viability of PC12 cells increased from 50.42 ± 5.51% for the AD group to 102.72 ± 4.34% for the 50 μM ginsenoside Rb1 group with cholesterol reduction. Our results suggested that ginsenoside Rb1 might function as an effective candidate to promote reverse cholesterol transport and lower ROS production, therefore providing a new insight into prevention and treatment of AD.

The membrane axis of Alzheimer's nanomedicine.

Alzheimer's disease (AD) is a major neurological disorder impairing its carrier's cognitive function, memory and lifespan. While the development of AD nanomedicine is still nascent, the field is evolving into a new scientific frontier driven by the diverse physicochemical properties and theranostic potential of nanomaterials and nanocomposites. Characteristic to the AD pathology is the deposition of amyloid plaques and tangles of amyloid beta (Aβ) and tau, whose aggregation kinetics may be curbed by nanoparticle inhibitors via sequence-specific targeting or nonspecific interactions with the amyloidogenic proteins. As literature implicates cell membrane as a culprit in AD pathogenesis, here we summarize the membrane axis of AD nanomedicine and present a new rationale that the field development may greatly benefit from harnessing our existing knowledge of Aβ-membrane interaction, nanoparticle-membrane interaction and Aβ-nanoparticle interaction.

Preferential Intercalation of Human Amyloid-β Peptide into Interbilayer Region of Lipid-Raft Membrane in Macromolecular Crowding Environment.

This study focuses on the interaction of human amyloid β-peptide (Aβ) with a lipid-raft model membrane under macromolecular crowding conditions that mimic the intracellular environment. Aβ is central to the development of Alzheimer's disease (AD) and has been studied extensively to determine the molecular mechanisms of Aβ-induced cellular dysfunctions underlying the pathogenesis of AD. According to evidence from spectroscopic studies, ganglioside clusters are key to the fibrillization process of Aβ. Gangliosides are a major component of glycosphingolipids and are acidic lipids of the central nervous system known to form so-called lipid rafts. In this study, the small unilamellar vesicle (SUV) membrane, composed of monosialogangliosides, cholesterol, and 1,2-dipalmitoyl- sn-glycero-3-phosphocholine, did not show any structural changes after the addition of Aβ under noncrowding conditions. However, the addition of Aβ under crowding conditions induced shape deformation and aggregation to SUV resulting in multilamellar stacking. The time evolution of the lamellar peak suggested the preferential cohesion or intercalation of the Aβ peptide into the interbilayer region. This phenomenon was only observed at the gel (Lβ) phase. These results suggest that an intracellular crowding environment promotes Aβ-membrane interaction and a selective accumulation of Aβ peptides into the interbilayer regions.

N-Terminal Charged Residues of Amyloid-β Peptide Modulate Amyloidogenesis and Interaction with Lipid Membrane.

Interactions of amyloid-β (Aβ) peptides and cellular membranes are proposed to be closely related with Aβ neurotoxicity in Alzheimer's disease. In this study, we systematically investigated the effect of the N-terminal hydrophilic region of Aβ40 on its amyloidogenesis and interaction with supported phospholipid bilayer. Our results show that modulation of the charge properties of the dynamic N-terminal region dramatically influences the aggregation properties of Aβ. Furthermore, our results demonstrate that the N-terminal charged residues play a crucial role in driving the early adsorption and latter remobilization of the peptide on membrane bilayer, and mediating the rigidity and viscoelasticity properties of the bound Aβ40 at the membrane interface. The results provide new mechanistic insight into the early Aβ-membrane interactions and binding, which may be critical for elucidating membrane-mediated Aβ amyloidogenesis in a physiological environment and unravelling the origin of Aβ neurotoxicity.

Amyloid-β Peptide Interaction with Lipid Bilayer Promotes Peptide Aggregation on the Surface and Modulates Lipid Behavior

Alzheimer's disease (AD) is an important, increasingly prevalent neurological disorder. Aggregation of Amyloid-β (Aβ) is important in etiology of AD and the interaction of these peptides with cell membranes is probably one of the key pathological events responsible for neuron cell death in AD. However, the molecular mechanism underlying the interaction is not known. The slow nature of conformational changes of protein and membrane lipids contributes to this void in the literature. To accelerate the membrane contribution to the conformational changes of Aβ without the loss of atomistic detail, we used the novel high mobility mimetic membrane (HMMM) model to investigate the Aβ-membrane interactions using molecular dynamic simulations. These membrane models increase lateral lipid movement by an order of magnitude while maintaining atomistic detail by modeling the lipid tails nearest the membrane center as a fluid organic solvent while maintaining the atomic description of the lipid head-groups. We built three systems: clusters of two and three unfolded Aβ40 peptides inside a membrane bilayer and an Aβ40 dimer with one peptide anchored to the membrane surface. The HMMM lipid composition used was PC:pPE:SM:CHOL 38:27:6:29. The transmembrane Aβ-peptides demonstrated rapid clustering (<50ns) with subsequent β-sheet formation between residues 18-22 of the monomers, concording with experimentally observed Aβ fibril structures and computationally determined dimer structures. The β-sheet formation can potentially lead to creation of a pore inside the membrane that can affect cellular function. The anchored dimer demonstrated increasing inter-peptide β-sheet content and subsequent movement toward the membrane surface, implying a mechanism for nucleation and aggregation of Aβ oligomers. The strong Aβ dimer-membrane interaction lowered the fluidity of the lipid molecules.

Binding of protofibrillar Aβ trimers to lipid bilayer surface enhances Aβ structural stability and causes membrane thinning.

Alzheimer's disease, a common neurodegenerative disease, is characterized by the aggregation of amyloid-β (Aβ) peptides. The interactions of Aβ with membranes cause changes in membrane morphology and ion permeation, which are responsible for its neurotoxicity and can accelerate fibril growth. However, the Aβ-lipid interactions and how these induce membrane perturbation and disruption at the atomic level and the consequences for the Aβ organization are not entirely understood. Here, we perform multiple atomistic molecular dynamics simulations on three protofibrillar Aβ9-40 trimers. Our simulations show that, regardless of the morphologies and the initial orientations of the three different protofibrillar Aβ9-40 trimers, the N-terminal β-sheet of all trimers preferentially binds to the membrane surface. The POPG lipid bilayers enhance the structural stability of protofibrillar Aβ trimers by stabilizing inter-peptide β-sheets and D23-K28 salt-bridges. The interaction causes local membrane thinning. We found that the trimer structure related to Alzheimer's disease brain tissue () is the most stable both in water solution and at membrane surface, and displays slightly stronger membrane perturbation capability. These results provide mechanistic insights into the membrane-enhanced structural stability of protofibrillar Aβ oligomers and the first step of Aβ-induced membrane disruption at the atomic level.

Influence of sequence and lipid type on membrane perturbation by human and rat amyloid β-peptide (1–42)

The hallmark characteristics of plaque formation and neuronal cell death in Alzheimer's disease (AD) are caused principally by the amyloid β-peptide (Aβ). Aβ sequence and lipid composition are essential variables to consider when elucidating the impact of biological membranes on Aβ structure and the effect of Aβ on membrane integrity. Atomistic molecular dynamics simulations testing two Aβ sequences, human and rat Aβ (HAβ and RAβ, respectively), and five lipid types were performed to assess the effect of these variables on membrane perturbation and potential link to AD phenotype differences based on differences in sequence. All metrics agree insomuch that monomeric HAβ and RAβ contribute to membrane perturbation by causing a more rigid, gel-like lipid phase. Differences between HAβ and RAβ binding on degree of membrane perturbation were based on lipid headgroup properties. Cholesterol was found to moderate the amount of perturbation caused by HAβ and RAβ in a model raft membrane. The difference in position of an arginine residue between HAβ and RAβ influenced peptide-membrane interactions and was determined to be the mediating factor in observed differences in lipid affinity and degree of membrane disruption. Overall, this work increases our understanding of the influence of sequence and lipid type on Aβ-membrane interactions and their relationship to AD.

Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides

Cellular membrane disruption induced by β-amyloid (Aβ) peptides has been considered one of the major pathological mechanisms for Alzheimer disease. Mechanistic studies of the membrane disruption process at a high-resolution level, on the other hand, are hindered by the co-existence of multiple possible pathways, even in simplified model systems such as the phospholipid liposome. Therefore, separation of these pathways is crucial to achieve an in-depth understanding of the Aβ-induced membrane disruption process. This study, which utilized a combination of multiple biophysical techniques, shows that the peptide-to-lipid (P:L) molar ratio is an important factor that regulates the selection of dominant membrane disruption pathways in the presence of 40-residue Aβ peptides in liposomes. Three distinct pathways (fibrillation with membrane content leakage, vesicle fusion, and lipid uptake through a temporarily stable ionic channel) become dominant in model liposome systems under specific conditions. These individual systems are characterized by both the initial states of Aβ peptides and the P:L molar ratio. Our results demonstrated the possibility to generate simplified Aβ-membrane model systems with a homogeneous membrane disruption pathway, which will benefit high-resolution mechanistic studies in the future. Fundamentally, the possibility of pathway selection controlled by P:L suggests that the driving forces for Aβ aggregation and Aβ-membrane interactions may be similar at the molecular level.

On the possible structural role of single chain sphingolipids Sphingosine and Sphingosine 1-phosphate in the amyloid-β peptide interactions with membranes. Consequences for Alzheimer’s disease development

A strong interplay between the neurodegerative effects of the amyloid β (Aβ) peptides and the cell lipid composition or metabolism has been evidenced in Alzheimer’s disease. This appears to be, in part, related to Aβ-membrane interactions. Recently, an influence of the two cell fate-modulating single-chain sphingolipids, sphingosine (Sph) and sphingosine 1-phosphate (S1P), on AD-related mechanisms has been reported. We have investigated the influence of Sph and S1P on the interaction of Aβ(1–42) with lipid model membranes. A fluorescent Aβ(1–42) binds to egg phosphatidylcholine (EPC) giant unilamellar vesicles containing Sph or S1P. With Sph, gel microdomains are present at low temperature and Aβ(1–42) binds preferentially to these domains, especially at their boundaries. With S1P, which displays single lipid phase morphology, Aβ(1–42) binding is uniform. The binding of Aβ(1–42) to EPC/sphingolipid large unilamellar vesicles was investigated by spectrofluorimetry using the 2 probes Laurdan and di-ANEPPS. With most lipid compositions the binding of Aβ(1–42) to LUVs appears superficial. However, with Sph, a deeper membrane penetration is observed. This deeper interaction is reversed to superficial by the simultaneous presence of S1P. It is suggested that the influence of single-chain sphingolipids in AD might be related to a selective interaction of Aβ(1–42) with sphingosine in membranes, that is antagonized by S1P. Such interaction might occur intracellularly for Aβ(1–42) monomers or oligomers and/or extracellularly for Aβ still part of APP. Aβ(1–42) might also influence microdomains by binding to their boundaries. The influence of the Sph/S1P balance on the Alzheimer pathology might be related in part to the differential interactions of Aβ(1–42) with Sph and S1P and their effects on membrane domains.

A High-Sensitive Detection of Several Tens of nM of Amyloid-Beta by Cantilever-Type Biosensor Immobilized DPPC Liposome Incorporated with Cholesterol

We have previously developed a NiCr strain-gauge cantilever-based biosensor with liposomes as sensing biomolecules immobilized on the cantilever surface to investigate time course of dynamic behaviour of amyloid-beta (1-40) protein on lipid membrane [1]. In this work, we attempt to improve effectively the sensitivity of the cantilever sensor by incorporating liposome with cholesterol to enhance Aβ-membrane interaction. Consequently, the sensitivity of the biosensor is significantly improved as 50-nM Aβ(1-40) has been detected. This result shows the possibility of detecting Aβ(1-40) in plasma of Alzheimer's disease (AD) patients because Aβ concentration in the plasma of AD patients is reported to be in the range from 75 to 100 nM [2].

Europium as an inhibitor of Amyloid-β(1-42) induced membrane permeation

Soluble Amyloid-beta (Aβ) oligomers are a source of cytotoxicity in Alzheimer’s disease (AD). The toxicity of Aβ oligomers may arise from their ability to interact with and disrupt cellular membranes mediated by GM1 ganglioside receptors within these membranes. Therefore, inhibition of Aβ–membrane interactions could provide a means of preventing the toxicity associated with Aβ. Here, using Surface Plasmon field-enhanced Fluorescence Spectroscopy, we determine that the lanthanide, Europium III chloride (Eu3+), strongly binds to GM1 ganglioside-containing membranes and prevents the interaction with Aβ42 leading to a loss of the peptides ability to cause membrane permeation. Here we discuss the molecular mechanism by which Eu3+ inhibits Aβ42-membrane interactions and this may lead to protection of membrane integrity against Aβ42 induced toxicity.

Influence of Sequence and Lipid Type on Membrane Perturbation by Human and Rat Amyloid β-Peptide (1-42)

The hallmark characteristics of plaque formation and neuronal cell death in Alzheimer's disease (AD) are caused principally by the amyloid β-peptide (Aβ). Current research focuses on understanding the interactions between Aβ and neuronal cell membranes, given the relationship between membrane perturbation and neurotoxicity. Aβ sequence and lipid composition are essential variables to consider when elucidating the impact of the biological membrane on Aβ structure and the effect of Aβ on membrane integrity. Atomistic molecular dynamics simulations testing two Aβ sequences (Human Aβ1-42) (HAβ) and Rat Aβ(1-42) (RAβ)), five lipid types, and totaling 9 μs in simulation time, were performed in order to explain the effect of these variables on membrane perturbation. All metrics used to assess membrane perturbation agree insomuch that it can be concluded that HAβ and RAβ contribute to membrane perturbation by causing a more rigid, gel-like lipid phase. The presence of cholesterol in a model raft membrane was found to moderate the amount of perturbation caused by HAβ and RAβ. Differences between HAβ and RAβ were seen based on lipid headgroup charge and hydrogen bond capacity. The position of arginine in the N-terminal region was determined to be the mediating factor in these differences in lipid affinity and disruption between HAβ and RAβ. Overall, this work rationalizes the influence of sequence and lipid type on Aβ-membrane interactions, providing mechanistic insight into the etiology of AD.