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Nicklas Österlund

PhD student

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Works at Department of Biochemistry and Biophysics
Email nicklas.osterlund@dbb.su.se
Visiting address Svante Arrhenius väg 16
Room A 361
Postal address Institutionen för biokemi och biofysik 106 91 Stockholm

About me

Ph.D. student in Biophysics 

Research group: Astrid Gräslund

M.Sc. in Molecular Biophysics (Stockholm University). Thesis: "Gas phase studies of the Amyloid-β peptide: oligomerization and interactions with membrane mimetics" (2017). 

Digital CV on LinkedIn

Primary scientific interest: Biomolecular mass spectrometry

Teaching

I teach in the course Biochemistry II (KB3003). I also supervise degree projects on the Bachelor and Master levels, feel free to contact me if you are interested! 

Research

Research suggests that it is the soluble Amyloid-β (Aβ) peptide oligomers and not the mature fibrils that are the main neurotoxic species in Alzheimer's disease (Haass & Selkoe, 2007). These peptide assemblies are formed in the early stages of aggregation, and the exact structures and oligomer distribution are not well known. Furthermore, it was recently found that interactions with SDS give rise to artifact oligomer species in gel electrophoresis analysis (Pujol-Pina et al. 2015), motivating the development of other methods.

I have developed a soft ionization mass spectrometry-based method where non-covalent interactions between Aβ-peptide monomers are retained in the gas phase. In this way, the oligomerization pathways of Aβ-peptides can be monitored in a time-depended way.

Current work is done to apply this method to study peptide behavior both in solution and in membrane model systems.  

Supervisors: 

Astrid Gräslund (Department of Biochemistry and Biophysics)

Mikael Oliveberg (Department of Biochemistry and Biophysics)

Leopold L. Ilag (Department of Materials and Environmental Chemistry)  

 

Publications

A selection from Stockholm University publication database
  • 2019. Nicklas Österlund (et al.). Journal of the American Chemical Society 141 (26), 10440-10450

    The mechanisms behind the Amyloid-beta (A beta) peptide neurotoxicity in Alzheimer's disease are intensely studied and under debate. One suggested mechanism is that the peptides assemble in biological membranes to form beta-barrel shaped oligomeric pores that induce cell leakage. Direct detection of such putative assemblies and their exact oligomeric states is however complicated by a high level of heterogeneity. The theory consequently remains controversial, and the actual formation of pore structures is disputed. We herein overcome the heterogeneity problem by employing a native mass spectrometry approach and demonstrate that A beta(1-42) peptides form coclusters with membrane mimetic detergent micelles. The coclusters are gently ionized using nanoelectrospray and transferred into the mass spectrometer where the detergent molecules are stripped away using collisional activation. We show that A beta(1-42) indeed oligomerizes over time in the micellar environment, forming hexamers with collision cross sections in agreement with a general beta-barrel structure. We also show that such oligomers are maintained and even stabilized by addition of lipids. A beta(1-40) on the other hand form significantly lower amounts of oligomers, which are also of lower oligomeric state compared to A beta(1-42) oligomers. Our results thus support the oligomeric pore hypothesis as one important cell toxicity mechanism in Alzheimer's disease. The presented native mass spectrometry approach is a promising way to study such potentially very neurotoxic species and how they could be stabilized or destabilized by molecules of cellular or therapeutic relevance.

  • 2019. Margit Kaldmae (et al.). Journal of the American Society for Mass Spectrometry 30 (8), 1385-1388

    Modulating protein ion charge is a useful tool for the study of protein folding and interactions by electrospray ionization mass spectrometry. Here, we investigate activation-dependent charge reduction of protein ions with the chemical chaperone trimethylamine-N-oxide (TMAO). Based on experiments carried out on proteins ranging from 4.5 to 35kDa, we find that when combined with collisional activation, TMAO removes approximately 60% of the charges acquired under native conditions. Ion mobility measurements furthermore show that TMAO-mediated charge reduction produces the same end charge state and arrival time distributions for native-like and denatured protein ions. Our results suggest that gas-phase collisions between the protein ions and TMAO result in proton transfer, in line with previous findings for dimethyl- and trimethylamine. By adjusting the energy of the collisions experienced by the ions, it is possible to control the degree of charge reduction, making TMAO a highly dynamic charge reducer that opens new avenues for manipulating protein charge states in ESI-MS and for investigating the relationship between protein charge and conformation.

  • 2019. Lin Liu (et al.). Chemical Communications 55 (35), 5147-5150

    The secondary structure content of proteins and their complexes may change significantly on passing from aqueous solution to the gas phase (as in mass spectrometry experiments). In this work, we investigate the impact of hydrophobic residues on the formation of the secondary structure of a real protein complex in the gas phase. We focus on a well-studied protein complex, the amyloid- (1-40) dimer (2A). Molecular dynamics simulations reproduce the results of ion mobility-mass spectrometry experiments. In addition, a helix (not present in the solution) is identified involving (19)FFAED(23), consistent with infrared spectroscopy data on an A segment. Our simulations further point to the role of hydrophobic residues in the formation of helical motifs - hydrophobic sidechains shield helices from being approached by residues that carry hydrogen bond sites. In particular, two hydrophobic phenylalanine residues, F19 and F20, play an important role for the helix, which is induced in the gas phase in spite of the presence of two carboxyl-containing residues.

  • 2019. Nicklas Österlund (et al.). Biochimica et Biophysica Acta - Proteins and Proteomics 1867 (5), 492-501

    The interplay between the amyloid-beta (A beta) peptide and cellular membranes have been proposed as an important mechanism for toxicity in Alzheimer's disease (AD). Membrane environments appear to influence A beta aggregation and may stabilize intermediate A beta oligomeric states that are considered to be neurotoxic. One important role for molecular biophysics within the field of A beta studies is to characterize the structure and dynamics of the A beta peptide in various states, as well as the kinetics of transfer between these states. Because biological cell membranes are very complex, simplified membrane models are needed to facilitate studies of A beta and other amyloid proteins in lipid environments. In this review, we examine different membrane-mimetic systems available for molecular studies of A beta. An introduction to each system is given, and examples of important findings are presented for each system. The benefits and drawbacks of each system are discussed from methodical and biological perspectives.

  • 2018. Nicklas Österlund (et al.). ACS Chemical Neuroscience 9 (7), 1680-1692

    The amphiphilic nature of the amyloid-beta (A beta) peptide associated with Alzheimer's disease facilitates various interactions with biomolecules such as lipids and proteins, with effects on both structure and toxicity of the peptide. Here, we investigate these peptide-amphiphile interactions by experimental and computational studies of A beta(1-40) in the presence of surfactants with varying physicochemical properties. Our findings indicate that electrostatic peptide-surfactant interactions are required for coclustering and structure induction in the peptide and that the strength of the interaction depends on the surfactant net charge. Both aggregation-prone peptide-rich coclusters and stable surfactant-rich coclusters can form. Only A beta(1-40) monomers, but not oligomers, are inserted into surfactant micelles in this surfactant-rich state. Surfactant headgroup charge is suggested to be important as electrostatic peptide-surfactant interactions on the micellar surface seems to be an initiating step toward insertion. Thus, no peptide insertion or change in peptide secondary structure is observed using a nonionic surfactant. The hydrophobic peptide-surfactant interactions instead stabilize the A beta monomer, possibly by preventing self-interaction between the peptide core and C terminus, thereby effectively inhibiting the peptide aggregation process. These findings give increased understanding regarding the molecular driving forces for A beta aggregation and the peptide interaction with amphiphilic biomolecules.

  • 2017. Cecilia Wallin (et al.). Scientific Reports 7

    Cigarette smoking is a significant risk factor for Alzheimer’s disease (AD), which is associated with extracellular brain deposits of amyloid plaques containing aggregated amyloid-β (Aβ) peptides. Aβ aggregation occurs via multiple pathways that can be influenced by various compounds. Here, we used AFM imaging and NMR, fluorescence, and mass spectrometry to monitor in vitro how Aβ aggregation is affected by the cigarette-related compounds nicotine, polycyclic aromatic hydrocarbons (PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV). All PAHs and metal ions modulated the Aβ aggregation process. Cd(II), Cr(III), and Pb(II) ions displayed general electrostatic interactions with Aβ, whereas Pb(IV) ions showed specific transient binding coordination to the N-terminal Aβ segment. Thus, Pb(IV) ions are especially prone to interact with Aβ and affect its aggregation. While Pb(IV) ions affected mainly Aβ dimer and trimer formation, hydrophobic toluene mainly affected formation of larger aggregates such as tetramers. The uncharged and hydrophilic nicotine molecule showed no direct interactions with Aβ, nor did it affect Aβ aggregation. Our Aβ interaction results suggest a molecular rationale for the higher AD prevalence among smokers, and indicate that certain forms of lead in particular may constitute an environmental risk factor for AD.

  • 2019. Nicoló Riboni (et al.). Scientific Reports 9

    Paper Spray Ionization (PSI) is commonly applied for the analysis of small molecules, including drugs, metabolites, and pesticides in biological fluids, due to its high versatility, simplicity, and low costs. In this study, a new setup called Solvent Assisted Paper Spray Ionization (SAPSI), able to increase data acquisition time, signal stability, and repeatability, is proposed to overcome common PSI drawbacks. The setup relies on an integrated solution to provide ionization potential and constant solvent flow to the paper tip. Specifically, the ion source was connected to the instrument fluidics along with the voltage supply systems, ensuring a close control over the ionization conditions. SAPSI was successfully applied for the analysis of different classes of biomolecules: amyloidogenic peptides, proteins, and N-glycans. The prolonged analysis time allowed real-time monitoring of processes taking places on the paper tip, such as amyloid peptides aggregation and disaggregation phenomena. The enhanced signal stability allowed to discriminate protein species characterized by different post translational modifications and adducts with electrophilic compounds, both in aqueous solutions and in biofluids, such as serum and cerebrospinal fluid, without any sample pretreatment. In the next future, application to clinical relevant modifications, could lead to the development of quick and cost-effective diagnostic tools.

Show all publications by Nicklas Österlund at Stockholm University

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Last updated: January 9, 2020

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