Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-β peptides in Alzheimer's disease. To gain a detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-β (Aβ)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to β-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aβ-mediated toxicity.

Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic

Department of Physics Birzeit University 71939 Birzeit Palestine

Institute of Biological Information Processing Forschungszentrum Jülich 52425 Jülich Germany

Institute of Biological Information Processing Forschungszentrum Jülich 52425 Jülich Germany;

Institute of Chemistry University of Miskolc 3515 Miskolc Egyetemváros Hungary

Institute of Theoretical and Computational Chemistry Heinrich Heine University Düsseldorf 40225 Düsseldorf Germany

Zobrazit více v PubMed

Barage S. H., Sonawane K. D., Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides 52, 1–18 (2015). PubMed

McLean C. A., et al. ., Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46, 860–866 (1999). PubMed

Kirkitadze M. D., Bitan G., Teplow D. B., Paradigm shifts in Alzheimer’s disease and other neurodegenerative disorders: The emerging role of oligomeric assemblies. J. Neurosci. Res. 69, 567–577 (2002). PubMed

Broersen K., Rousseau F., Schymkowitz J., The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer’s disease: Oligomer size or conformation? Alzheimers Res. Ther. 2, 12 (2010). PubMed PMC

Müller-Schiffmann A., et al. ., Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain 139, 509–525 (2016). PubMed

Brinkmalm G., et al. ., Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer’s brain. Brain 142, 1441–1457 (2019). PubMed PMC

Bitan G., Teplow D. B., Rapid photochemical cross-linking—A new tool for studies of metastable, amyloidogenic protein assemblies. Acc. Chem. Res. 37, 357–364 (2004). PubMed

Ono K., Condron M. M., Teplow D. B., Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc. Natl. Acad. Sci. U.S.A. 106, 14745–14750 (2009). PubMed PMC

O’Nuallain B., et al. ., Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils. J. Neurosci. 30, 14411–14419 (2010). PubMed PMC

Vázquez de la Torre A., et al. ., Direct evidence of the presence of cross-linked a β dimers in the brains of Alzheimer’s disease patients. Anal. Chem. 90, 4552–4560 (2018). PubMed

Castello F., et al. ., Two-step amyloid aggregation: Sequential lag phase intermediates. Sci. Rep. 7, 40065 (2017). PubMed PMC

Yang J., et al. ., Direct observation of oligomerization by single molecule fluorescence reveals a multistep aggregation mechanism for the yeast prion protein ure2. J. Am. Chem. Soc. 140, 2493–2503 (2018). PubMed PMC

Nasica-Labouze J., et al. ., Amyloid β protein and Alzheimer’s disease: When computer simulations complement experimental studies. Chem. Rev. 115, 3518–3563 (2015). PubMed PMC

Nguyen P. H., et al. ., Amyloid oligomers: A joint experimental/computational perspective on Alzheimer’s disease, Parkinson’s disease, type II diabetes, and amyotrophic lateral sclerosis. Chem. Rev. 121, 2545–2647 (2021). PubMed PMC

Lee S. J. C., Nam E., Lee H. J., Savelieff M. G., Lim M. H., Towards an understanding of amyloid-β oligomers: Characterization, toxicity mechanisms, and inhibitors. Chem. Soc. Rev. 46, 310–323 (2017). PubMed

Owen M. C., et al. ., Effects of in vivo conditions on amyloid aggregation. Chem. Soc. Rev. 48, 3946–3996 (2019). PubMed

Korade Z., Kenworthy A. K., Lipid rafts, cholesterol, and the brain. Neuropharmacology 55, 1265–1273 (2008). PubMed PMC

Posse de Chaves E., Sipione S., Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett. 584, 1748–1759 (2010). PubMed

Kao Y. C., Ho P. C., Tu Y. K., Jou I. M., Tsai K. J., Lipids and Alzheimer’s disease. Int. J. Mol. Sci. 21, 1505 (2020). PubMed PMC

Paul A., Samantray S., Anteghini M., Khaled M., Strodel B., Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment. Chem. Sci. (Camb.) 12, 6652–6669 (2021). PubMed PMC

Samantray S., Yin F., Kav B., Strodel B., Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations. J. Chem. Inf. Model. 60, 6462–6475 (2020). PubMed

Strodel B., Amyloid aggregation simulations: Challenges, advances and perspectives. Curr. Opin. Struct. Biol. 67, 145–152 (2021). PubMed

Koldsø H., Shorthouse D., Hélie J., Sansom M. S., Lipid clustering correlates with membrane curvature as revealed by molecular simulations of complex lipid bilayers. PLOS Comput. Biol. 10, e1003911 (2014). PubMed PMC

Ingólfsson H. I., et al. ., Computational lipidomics of the neuronal plasma membrane. Biophys. J. 113, 2271–2280 (2017). PubMed PMC

Barz B., Wales D. J., Strodel B., A kinetic approach to the sequence-aggregation relationship in disease-related protein assembly. J. Phys. Chem. B 118, 1003–1011 (2014). PubMed PMC

Barz B., Liao Q., Strodel B., Pathways of amyloid-β aggregation depend on oligomer shape. J. Am. Chem. Soc. 140, 319–327 (2018). PubMed

Illig A. M., Strodel B., Performance of Markov state models and transition networks on characterizing amyloid aggregation pathways from MD data. J. Chem. Theory Comput. 16, 7825–7839 (2020). PubMed

Jämbeck J. P., Lyubartsev A. P., An extension and further validation of an all-atomistic force field for biological membranes. J. Chem. Theory Comput. 8, 2938–2948 (2012). PubMed

Ermilova I., Lyubartsev A. P., Extension of the slipids force field to polyunsaturated lipids. J. Phys. Chem. B 120, 12826–12842 (2016). PubMed

Egawa J., Pearn M. L., Lemkuil B. P., Patel P. M., Head B. P., Membrane lipid rafts and neurobiology: Age-related changes in membrane lipids and loss of neuronal function. J. Physiol. 594, 4565–4579 (2016). PubMed PMC

Pata V., Dan N., Effect of membrane characteristics on phase separation and domain formation in cholesterol-lipid mixtures. Biophys. J. 88, 916–924 (2005). PubMed PMC

Ohvo-Rekilä H., Ramstedt B., Leppimäki P., Slotte J. P., Cholesterol interactions with phospholipids in membranes. Prog. Lipid Res. 41, 66–97 (2002). PubMed

Coles M., Bicknell W., Watson A. A., Fairlie D. P., Craik D. J., Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is? Biochemistry 37, 11064–11077 (1998). PubMed

Miyashita N., Straub J. E., Thirumalai D., Structures of β−amyloid peptide 1–40, 1–42, and 1–55 – the 672–726 fragment of app – in a membrane environment with implications for interactions with γ-secretase. J. Am. Chem. Soc. 131, 17843–17852 (2009). PubMed PMC

Strodel B., Lee J. W. L., Whittleston C. S., Wales D. J., Transmembrane structures for Alzheimer’s Aβ(1-42) oligomers. J. Am. Chem. Soc. 132, 13300–13312 (2010). PubMed

Nagel-Steger L., Owen M. C., Strodel B., An account of amyloid oligomers: Facts and figures obtained from experiments and simulations. ChemBioChem 17, 657–676 (2016). PubMed

Kakeshpour T., et al. ., A lowly populated, transient β-sheet structure in monomeric aβ1-42 identified by multinuclear NMR of chemical denaturation. Biophys. Chem. 270, 106531 (2020). PubMed PMC

Urbanc B., et al. ., Molecular dynamics simulation of amyloid beta dimer formation. Biophys. J. 87, 2310–2321 (2004). PubMed PMC

Côté S., Laghaei R., Derreumaux P., Mousseau N., Distinct dimerization for various alloforms of the amyloid-beta protein: Aβ1–40, β1–42, and β1–40(d23n). J. Phys. Chem. B 116, 4043–4055 (2012). PubMed

Man V. H., Nguyen P. H., Derreumaux P., High-resolution structures of the amyloid-β–42 dimers from the comparison of four atomistic force fields. J. Phys. Chem. B 121, 5977–5987 (2017). PubMed PMC

Mehrazma B., Rauk A., Exploring amyloid-β dimer structure using molecular dynamics simulations. J. Phys. Chem. A 123, 4658–4670 (2019). PubMed

Rauscher S., et al. ., Structural ensembles of intrinsically disordered proteins depend strongly on force field: A comparison to experiment. J. Chem. Theory Comput. 11, 5513–5524 (2015). PubMed

Lührs T., et al. ., 3D structure of Alzheimer’s amyloid-β (1-42) fibrils. Proc. Natl. Acad. Sci. U.S.A. 102, 17342–17347 (2005). PubMed PMC

Paravastu A. K., Leapman R. D., Yau W. M., Tycko R., Molecular structural basis for polymorphism in Alzheimer’s beta-amyloid fibrils. Proc. Natl. Acad. Sci. U.S.A. 105, 18349–18354 (2008). PubMed PMC

Tarus B., Straub J. E., Thirumalai D., Structures and free-energy landscapes of the wild type and mutants of the Aβ (21-30) peptide are determined by an interplay between intrapeptide electrostatic and hydrophobic interactions. J. Mol. Biol. 379, 815–829 (2008). PubMed PMC

Gremer L., et al. ., Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science 358, 116–119 (2017). PubMed PMC

Rezaei-Ghaleh N., Parigi G., Zweckstetter M., Reorientational dynamics of amyloid-β from NMR spin relaxation and molecular simulation. J. Phys. Chem. Lett. 10, 3369–3375 (2019). PubMed PMC

Hong S., et al. ., Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82, 308–319 (2014). PubMed PMC

Kedia N., Almisry M., Bieschke J., Glucose directs amyloid-β into membrane-active oligomers. Phys. Chem. Chem. Phys. 19, 18036–18046 (2017). PubMed PMC

Ikeda K., Yamaguchi T., Fukunaga S., Hoshino M., Matsuzaki K., Mechanism of amyloid β-protein aggregation mediated by GM1 ganglioside clusters. Biochemistry 50, 6433–6440 (2011). PubMed

Matsuzaki K, Formation of toxic amyloid fibrils by amyloidβ protein on ganglioside clusters. Int. J. Alzheimers Dis. 2011, 956104 (2011). PubMed PMC

Cebecauer M., Hof M., Amaro M., Impact of GM1 on membrane-mediated aggregation/oligomerization of β-amyloid: Unifying view. Biophys. J. 113, 1194–1199 (2017). PubMed PMC

Sokolova T. V., Zakharova I. O., Furaev V. V., Rychkova M. P., Avrova N. F., Neuroprotective effect of ganglioside GM1 on the cytotoxic action of hydrogen peroxide and amyloid beta-peptide in PC12 cells. Neurochem. Res. 32, 1302–1313 (2007). PubMed

Kreutz F., et al. ., Amyloid-β induced toxicity involves ganglioside expression and is sensitive to GM1 neuroprotective action. Neurochem. Int. 59, 648–655 (2011). PubMed

Yang R., et al. ., Monosialoanglioside improves memory deficits and relieves oxidative stress in the hippocampus of rat model of Alzheimer’s disease. Neurol. Sci. 34, 1447–1451 (2013). PubMed

Lee J., et al. ., CHARMM-GUI input generator for NAMD, GROMACS, AMBER, openMM, and CHARMM/openMM simulations using the CHARMM36 additive force field. J. Chem. Theory Comput. 12, 405–413 (2016). PubMed PMC

Carballo-Pacheco M., Strodel B., Advances in the simulation of protein aggregation at the atomistic scale. J. Phys. Chem. B 120, 2991–2999 (2016). PubMed

Sengupta U., Carballo-Pacheco M., Strodel B., Automated Markov state models for molecular dynamics simulations of aggregation and self-assembly. J. Chem. Phys. 150, 115101 (2019). PubMed

Abraham M. J., et al. ., GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1, 19–25 (2015).

Huang J., et al. ., CHARMM36m: An improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017). PubMed PMC

Klauda J. B., et al. ., Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types. J. Phys. Chem. B 114, 7830–7843 (2010). PubMed PMC

Bussi G., Donadio D., Parrinello M., Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007). PubMed

Berendsen H. J., Postma J., van Gunsteren W. F., DiNola A., Haak J. R., Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684–3690 (1984).

Antila H., et al. ., Headgroup structure and cation binding in phosphatidylserine lipid bilayers. J. Phys. Chem. B 123, 9066–9079 (2019). PubMed

Zhang Y., Sagui C., Secondary structure assignment for conformationally irregular peptides: Comparison between DSSP, STRIDE and KAKSI. J. Mol. Graph. Model. 55, 72–84 (2015). PubMed

Möckel C., et al. ., Integrated NMR, fluorescence, and molecular dynamics benchmark study of protein mechanics and hydrodynamics. J. Phys. Chem. B 123, 1453–1480 (2019). PubMed

Bastian M., et al. ., Gephi: An open source software for exploring and manipulating networks. Proc. Third Int. ICWSM Conf. 8, 361–362 (2009).

Humphrey W., Dalke A., Schulten K., VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996). PubMed