Amyloid-beta peptide (25-35) triggers a reorganization of lipid membranes driven by temperature changes

doi:10.21203/rs.3.rs-886431/v1

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Amyloid-beta peptide (25-35) triggers a reorganization of lipid membranes driven by temperature changes

https://doi.org/10.21203/rs.3.rs-886431/v1

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The amyloid-beta peptide (Aβ) is considered a key factor in Alzheimer's disease (AD) ever since the discovery of the disease. The understanding of its damaging influence has however shifted recently from large fibrils observed in the inter-cellular environment to the small oligomers interacting with a cell membrane. We studied the effect of temperature on the latter interactions by evaluating the structural characteristics of zwitterionic phosphatidylcholine (PC) membranes with incorporated Aβ25-35 peptide. By means of small angle neutron scattering (SANS), we have observed for the first time a spontaneous reformation of extruded unilamellar vesicles (EULVs) to discoidal bicelle-like structures (BLSs) and small unilamellar vesicles (SULVs). These changes in the membrane self-organization happen during the thermodynamic phase transitions of lipids and only in the presence of the peptide. We interpret the dramatic changes in the membrane's overall shape with parallel changes in its thickness as the Aβ25-35 triggered membrane damage and a consequent reorganization of its structure. The suggested process is consistent with an action of separate peptides or a small number of peptide oligomers rather than the result of a large Aβ fibril.

Nuclear Medicine & Medical Imaging

Biological Chemistry

Alzheimer's disease (AD)

phosphatidylcholine (PC)

SULVs

bicelle-like structures (BLSs)

amyloid precursor protein (APP)

One of the hallmarks of Alzheimer's disease (AD) is a self-aggregation of the amyloid-β (Aβ) peptide into the large extracellular β-sheet fibrils^1,2. Aβ peptide is known to be cleaved enzymatically from a transmembrane amyloid precursor protein (APP) in 1–40 and 1–42 isoforms. The transformation from the membrane monomeric peptide to an aggregated fibril outside the membrane, however, has yet to be understood. It was shown nevertheless, that these peptides and their interactions with the membrane in particular, may play a major role in triggering the onset of AD³.

The changes in membrane functionality most likely originate in the structural properties of the membrane. For example, the thermodynamic phase of lipids plays one of the starring roles in determining the membrane’s structural properties⁴. At the assistance of increasing temperature, the crystalline phase passes from a highly ordered structure to the liquid-crystalline phase typical of the high disorder. The ability of the Aβ to interact with the membrane was found to depend on the structural and elasto-mechanical properties of the membrane, thus its thermodynamic phase ^5,6. An intriguing possibility would be to look for a membrane state that will retain the peptides in their monomeric form.

On the other hand, a mechanism of action proposing the membrane damage by monomeric Aβ or their small oligomers has been proposed recently^7,8. Our study focuses on such pre-clinical AD stages where Aβ appears in its non-aggregated forms, and we scrutinize the peptide-membrane interactions instead of those between the peptides. Accordingly, the care is taken to incorporate Aβ into the membrane during its formation rather than adding it afterwards^5,9−11. After initial preparation and stabilization, our model membrane systems do not appear to be affected dramatically by the accommodation of Aβ. This was however proposed to change during the membrane phase transition¹²

Despite a long-lasting debate on the character of the lipid membrane phase transition, the changes of physico-chemical properties of the membrane do not result in its disruption. The interaction with its additional components may nevertheless introduce some abrupt structural changes^13,14. Our report documents such changes triggered by the presence of Aβ_25-35 during the phase transitions of the underlying lipid matrix. The observed effect of Aβ peptide fragmenting the otherwise cohesive membrane may be a key point in understanding the role of membrane-peptide interactions in AD.

The Aβ_25-35 was chosen to mimic the smallest transmembrane part of the Aβ peptide while still including its toxic fragment. The studies of the conformational changes of Aβ_25-35 and Aβ_1-42 in the presence of the lipid membrane show no difference in the behavior between the full and the short fragment¹⁵. The neuronal cell membrane is modeled by one of its main zwitterionic components, namely phosphatidylcholine (PC), with either 16:0 or 14:0 chains that are also ones of the most represented lipidomic elements in the human brain¹⁶. Although the most physiological combination of hydrocarbon chains appears to be that of 16:0 and 18:1, constructing the membrane of DPPC (i.e., diC16:0PC) or DMPC (i.e., diC14:0PC) allowed us to regulate the phase transition temperature in a physiological range and examine its effect purposely. Their pretransition and main phase transition temperatures are 34.2 and 41.4°C in the case of DPPC, and 14.3 and 23.9°C in the case of DMPC, respectively¹⁷. The lipid membranes with Aβ peptide incorporated initially were forced to form ULVs of well-defined sizes and bilayer thicknesses by the extrusion through 500 Å pores. The diluted suspension of EULVs was utilized as the best model for structural investigations by SANS that offers the desired structural parameters.

The SANS curves were collected at various temperatures below and above the mentioned phase transitions for a control system of neat DPPC or DMPC system (DPPC or DMPC, respectively) and systems of the Aβ_25-35 loaded DPPC or DMPC bilayers (DPPC/Aβ_25-35 or DMPC/Aβ_25-35, respectively) as shown in Fig. 1a and 1c, and 1b and 1d, respectively. While the SANS curves for the neat lipid systems (Fig. 1a and 1c) at various temperatures display differences exclusively in a high-q region (above 0.1 Å^-1), those collected for the peptide included systems (Fig. 1b and 1d) display significant changes also in a low-q region (below 0.02 Å^-1); see also Fig. S1. Similar changes in the SANS curves were observed for some systems under certain conditions previously and were connected to the formation of bicelles^13,14,18,19. By virtue of the scattering experiment principles, the low-q region of presented data is influenced for the most part by a form factor of the overall ULV, while the high-q region is influenced by a form factor of the bilayer, and its thickness in particular. Based on the changes observed in our SANS curves, we can thus evaluate the temperature induced variations in the membrane thickness, and ULVs’ size and shape.

The membrane thicknesses were obtained at first from the small-angle Kratky-Porod approximation for unoriented lamellar objects²⁰. This approach is very sensitive to a possible Bragg-scattering peak that would skew the data analysis. The lack of its detection, however, allows us to conclude the absence of long-range order in our systems. On the other hand, this approach is not suitable for extracting further information regarding the object shape and size, which prompted us to employ a 3-shell vesicle model²¹. It is worth noting nevertheless, that the changes in the obtained membrane thicknesses were found independent of the approximation model used (see Fig. S2 of the supplement).

The changes to the bilayer thickness are shown in Fig. S3 of the supplement. Note that the measurements at the same temperatures result in a different number of points in different thermodynamic phases for the two lipid systems (i.e., there is 1 point below and 3 points above the main phase transition in the case of DMPC bilayers, while 3 points below and 1 point above the main phase transition in the case of DPPC bilayers). We thus display these results as a function of reduced temperature relative to the main transition of a given lipid in Fig. 2. This representation makes it apparent, that the behavior of bilayer thickness for the two systems is similar when the comparison is done within the same phase, only shifted by ~ 4Å due to differences in hydrocarbon chain lengths²². As expected, the bilayer thickness decreases within highly ordered gel (L_β) and/or ripple (P_β’) phases gradually at first due to a continuously increasing disorder of hydrocarbon chains^23,24. A sudden change in the bilayer thickness is then observed upon DMPC and DPPC transitioning from P_β’ to liquid-crystalline (L_α) phase²³. Finally, the thickness increases during the reverse transition. It is worth noting, the thickness variations due to these temperature changes are fully reversible in the case of neat lipid systems (empty symbols in Fig. 2a).

Intriguingly, a different behavior was observed in the case of Aβ_25-35 loaded bilayers. At first, DPPC/Aβ_25-35 bilayer thickness appears to increase minimally by the incorporation of Aβ (see the solid red circles at the initial two points in Fig. 2a). During the heating, however, the thickness shows a startling increase over the temperature interval where the neat DPPC bilayer undergoes its L_β–P_β’ pretransition (T-T_mDPPC = -7 ºC)¹⁷. It is of the utmost interest to note, that in contrast to the DPPC system, the heating process brought up the changes not only to the bilayer thickness but also to the overall shape of ULVs as can be detected already in Fig. 1b (low-q region). The SANS curves collected at T = 40°C could be fitted with the bilayered vesicle model poorly, while the satisfactory results were obtained by employing a model of randomly oriented cylindrical shells with a circular cross-section (bicelle-like structures - BLSs)²⁵. The dramatic changes to the membrane thickness were, however, independent of the model describing an overall shape of the membrane (see Fig. S2 of the supplement). The initially produced EULVs of approximately 800 Å outer diameter appear to transition to BLSs with their outer diameter of about 400 Å upon heating the DPPC/Aβ_25-35 to 40°C as shown in Fig. S4a of the supplement, and in Fig. 2b (T-T_mDPPC = -1 ºC, solid red circles). This is in a stark contrast to the DPPC system that only forms ULVs with their sizes varying by less than 200 Å over the entire range of temperatures studied.

It is interesting to note that a similar transition was not observed in the case of DMPC/Aβ_25-35. In fact, Fig. 2 together with Fig. S4b suggest this system occurring in the form of BLSs from the very first measurement. We argue this being a result of the extrusion procedure performed at room temperature, which likely matches or even exceeds the system main phase transition. Correspondingly, the DMPC/Aβ_25-35 system may indeed form BLSs already at our initial measurements, as corroborated by the bilayer being ~ 7 Å thicker than that made of DMPC (solid and empty diamonds on Fig. 2a) and the outer diameter of lipid aggregates being ~ 400 Å (Fig. 2b) – similar to the parameters of BLSs in the case of DPPC/Aβ_25-35. This observation then suggests the lipid phase transition as a universal feature driving the membrane reorganization triggered by the presence of Aβ_25-35.

We support our claims of observing the BLSs in the SANS results by observations employing transmission electron microscopy (TEM). The TEM images collected from the samples after their examinations by SANS are presented in Fig. 3. They confirm the structure picture revealed by SANS, showing the objects consistent with the spherical bilayered vesicles in the case of neat DMPC bilayers, and flat discoidal objects when Aβ_25-35 was incorporated. The DMPC vesicle sizes vary around 900 Å, and the sizes of disc-like structures are around 500 Å, which are in a good agreement with our SANS results. Note that the TEM sample preparation procedure may provide slightly different parameters because of additional steps (e.g., dilution, negative staining) employed in the sample preparation.

The formation of BLSs has been proposed as a precursor to the formation of SULVs with low polydispersity²⁶. Indeed, our SANS curves for DPPC/Aβ_25-35 and DMPC/Aβ_25-35 systems could be fitted satisfactorily with the bilayered vesicle model again after heating the system above the main transition from P_β’ to L_α phase of neat lipid bilayers¹⁷. Our best fit results demonstrate a narrow distribution of ULV outer diameters around a mean value as small as 200 Å (Fig. 2b). At the same time, the bilayer thickness of such SULVs decreases rapidly (Fig. 2a).

Upon cooling the system down again, and further cycling of temperatures between 20 and 50°C, the corresponding SANS curves corroborate a scenario of the thick-bilayer BLSs at low temperatures and thin-bilayer SULVs at T = 50°C. We note that the very same samples were examined also utilizing some complementary small angle X-ray scattering measurements, whose results suggested the same behavior (Fig. S5 of the supplement). It is also worth noting that the system has not reached the initial form of EULVs anymore, while it remained to transition between the BLSs and SULVs (see Fig. 4).

Yoda et al.⁵ suggested that the Aβ binds to lipid membranes predominantly in the L_β and P_β’ phase and does not interact with them in the L_α phase. Our experimental results show the first and irreversible changes to the DPPC/Aβ_25-35 membranes over the temperature range corresponding to the transition of neat DPPC bilayers from L_β to P_β’ phase. It suggests then that these changes are related to the thermodynamic properties of the membrane itself. We have performed some MD simulations with the DPPC/Aβ_25-35 system at different temperatures in an attempt to shed light on these interactions. Simulation results confirm the bilayer thickness increase due to the addition of the peptide and its decrease upon heating the system (Fig. S6 of the supplement). This then indeed supports an essential role of the thermodynamic properties of the membrane through regulating its thickness.

The rapid increase of the bilayer thickness accompanied by the change of membrane organization, or a significant shift in the initial location of the peptides was however absent. This could be explained by the limitations of our full-atom simulations that examined a small patch of the membrane only, while some coarse-grain simulations must be employed to access the large-scale aggregations¹³. Our simulations nevertheless reconfirm the plausibility of Aβ_25-35 incorporation to the DPPC membrane (Fig. 5).

One of the important membrane properties that changes during the phase transition is a lateral diffusion. The Aβ_25-35 and Aβ_22-40 have been shown to increase the lateral diffusion in liquid crystalline membranes²⁷, and Aβ_22-40 was suggested to decrease it in membranes near their main phase transition¹². In addition, the Aβ secondary structure transforms from the α-helix to irregular at the main phase transition⁵. The structural and dynamic changes to the membranes during the phase transition between the less diffusive, while more rigid membrane accompanied also with a relatively rigid α-helix peptide, and the more diffusive fluid membrane with a flexible irregular peptide may be a foundation to a temporary membrane breakage. It is intriguing then to speculate the less flexible α-helix peptide at low temperatures driving a membrane reformation into the BLSs rimmed with the Aβ. This assumption was indeed proposed recently ¹⁰. Such a scenario is consistent also with the Aβ-membrane interactions reported at low temperatures⁵. On the other hand, the increased flexibility of both the membrane and Aβ due to an increased temperature may be a reason for the membrane to reform into the SULVs with canonically distributed Aβ, as we have observed at a high temperature in the agreement with findings in the literature²⁸.

Our SANS experiments performed at temperatures ensuing the variation of membrane thermodynamic properties suggest for the first time dramatic changes to the structure of membrane organization due to Aβ_25-35 incorporation. The DPPC/Aβ_25-35 membranes undergo an initial transition from EULVs (outer diameter of 800 Å) to BLSs (outer diameter of 400 Å), and both DPPC/Aβ_25-35 and DMPC/Aβ_25-35 membranes transition reversibly between the BLSs and SULVs (outer diameter of 200Å) during their phase transitions. Our observations are consistent with membrane damage and its subsequent reformation being caused by the separate peptides or their small oligomers.

Sample preparation. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) from Avanti Polar Lipids (Alabaster, AL) and amyloid-beta peptide segment 25–35 (Aβ_25-35) from Abbiotec (Escondido, CA) were purchased in lyophilized powder form and used without further purification. Organic solvents 2,2,2-trifluoroethanol (TFE), chloroform, and trifluoroacetic acid (TFA) were purchased from Sigma-Aldrich Chemie Gmbh (Schnelldorf, Germany).

The lipid was dissolved in an organic solvents mixture of chloroform:TFE = 1:1 (by volume) in glass vials at the total concentration of 50 mg/ml. The peptide was subjected to a pretreatment procedure, according to which it was dissolved in TFA and treated in the ultrasonic bath for 10–12 min to enforce a peptide disaggregation²⁹. The acid solution was then evaporated under a stream of nitrogen and the peptide was redissolved in the same organic solvent as the lipid at a concentration of 1.6 mg/ml.

The lipid and Aβ_25-35 solutions were mixed in microtubes at the 0.5 mol% concentration of peptide, which was selected to diminish the possibility of its spontaneous aggregation and bilayer structure disruption³⁰. The mixtures were dried to dryness and placed under a vacuum for 12 hours for removing the remaining solvent. The lipid/Aβ_25-35 films were then hydrated with D₂O at their total concentration of 1% (by mass). The hydrated samples were frozen and thawed in several cycles accompanied by thorough vortexing. The attention was paid to keeping the samples at room temperatures at all times during the preparation procedure (i.e., below the DPPC phase transition from its gel phase).

The resulting multilamellar solutions were finally extruded into unilamellar vesicles (ULVs). The Avanti Mini Extruder® was utilized at room temperature without heating, and fitted with polycarbonate membranes of sequentially decreasing pore sizes: 2000 Å, 1000 Å, and 500 Å. Only the finally extruded ULVs were used in the measurements. Independent samples of all systems were prepared for several experimental cycles.

Small angle neutron scattering experiments. SANS measurements were performed at the time-of-flight spectrometer YuMO at the IBR-2 pulsed reactor (JINR, Dubna, Russia)³¹. The beam of neutrons was formed by a set of two pinhole collimators of diameters 40 and 14 mm. The neutrons scattered by the sample were detected with two circular wire-ring detectors placed at distances 4.5 and 13 m from the sample. An absolute intensity calibration was performed with the vanadium standard during the raw data treatment in the SAS program³². The liquid samples were contained in 2-mm-thick flat quartz cuvettes (Hellma) and held in the multipositional sample holder connected to the Lauda liquid thermostat with temperature controller Pt-100 that allows for a temperature accuracy of ± 0.03ºC.

The different samples of both systems of interest were examined in several independent experimental cycles. The standardly accessible range of scattering vector q from 0.007 to 0.5 Å^-1 was extended in one of the measurements down to 0.005 Å^-1 utilizing a cold-moderator setup³³. This low-q enhanced data allowed us to corroborate our conclusions regarding the overall shape of examined objects (see Fig. S1 of the supplement). The collected scattering curves were corrected for background scattering from the buffer solution. The analysis of final SANS curves including the error analysis was performed with the SASFit program²⁵ using the models of bilayered vesicles or randomly oriented cylindrical core-shell objects with a circular cross-section (see Fig. S7 of the supplement for the detailed description of models employed).

Transmission electron microscopy.

DMPC (1 wt%) and DMPC/Aβ_25-35 (1 wt% total, and 3 mol% of Aβ_25-35) solutions were diluted in deionized water to a final concentration of 67 µg/ml. The samples were set on carbon-coated 200 mesh copper grids with a thin layer of carbon 10 nm. Grids were treated by glow discharge using a PELCO easiGlow glow discharge cleaning system for a total of 25 seconds at 15 mA. Samples were placed onto the grids immediately following the glow discharge. The drop of solution was applied for 2 minutes to the metal-coated face of the grid. Samples were stained with aqueous uranyl acetate (2%) by soaking in solution for 1 minute. Then, the grid with the sample was washed in deionized water for 1 min and air dried.

The micrographs were recorded at a magnification of 10,000–40,000 in Tecnai Polara G2 (FEI) transmission electron microscope (FEG cathode source operated at 300 eV of accelerating voltage) with the Gatan Orius 4k x 2.67k digital camera. The specimen received a dose of electrons 10e/Å² in each exposure.

Molecular dynamics simulations.

The behavior of Aβ_25-35 peptide in a model phospholipid membrane and its effect on membrane properties was investigated also utilizing a set of MD simulations. The simulations were performed using the GROMACS 2019.3 software package³⁴ and the all-atom CHARMM36m force field³⁵. The initial configurations and topologies of the model bilayers containing 256 DPPC molecules, 8 Aβ_25-35 molecules, and 50 water molecules per lipid were set up using Membrane Builder from the CHARMM-GUI³⁶. The bonds with H-atoms were constrained using the LINCS algorithm, force-based switching functions with a range of 1.0 − 1.2 nm were used for the Lennard-Jones interactions, and long-range electrostatic interactions were calculated using the particle mesh Ewald algorithm. Periodic boundary conditions were used in all three dimensions. The integration of the motion equations was performed using the leapfrog algorithm with a time step of 2 fs. The systems were coupled to the Berendsen thermostat at 293 K, 303 K, 313 K, and 323 K with a coupling time constant of 1 ps, while the pressure was maintained at 1 bar using a semi-isotropic pressure coupling with the Berendsen barostat. For production runs, the thermostat and barostat were switched to those of Nose-Hoover and Parrinello–Rahman, respectively. Equilibration was performed for 50 ns and 100 ns for the pure bilayers and peptide containing bilayers, respectively. The production simulations were carried out for up to 200 ns for pure lipid membranes, and 1 µs for the Aβ_25-35 containing systems. The last 100 ns and 500 ns, respectively, were used for system analysis. The bilayer thickness was calculated based on the distribution density of phosphorus atoms of the lipid head groups using the in-house tools.

Acknowledgments

This work has been supported by the Russian Science Foundation [grant number 19-72-20186]. We acknowledge the utilization of IBR-2 facility through its user program and access to the computational heterogeneous cluster HybriLIT.

Author Contributions

O.I., N.K., T.N.M., D.S., A.I.K. designed the research; O.I., N.K. wrote the manuscript; O.I., T.N.M., E.V.E., T.K., P.H., D.S. performed the sample preparations and small angle scattering experiments; A.T., A.R. performed the TEM experiments, D.R.B. carried out the M.D. calculations. All the authors approved the manuscript.

Additional information

Supplementary Information. Supplementary materials to this article may be found online.

Declaration of competing interest

The authors declare no conflicts of interest in regard to this manuscript.

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Amyloid-beta peptide (25-35) triggers a reorganization of lipid membranes driven by temperature changes

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