Marcus Fändrich

Universität Ulm, Ulm, Baden-Württemberg, Germany

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Publications (83)495.08 Total impact

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    ABSTRACT: Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.
    Proceedings of the National Academy of Sciences 09/2015; 112(38). DOI:10.1073/pnas.1503455112 · 9.67 Impact Factor
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    ABSTRACT: Solvation and hydration are key factors for determining the stability and folding of proteins, as well as the formation of amyloid fibrils and related polypeptide aggregates. Using attenuated total reflectance Fourier-transform infrared (ATR-FTIR) and solid-state (ss)NMR spectroscopy, we find that the Aβ peptide experiences a remarkable conformational switch from β to α secondary structure upon solvent removal by lyophilization of oligomers. This transition is, contrary to Aβ fibrils, independent of concentration of organic co-solvents or co-solutes, and reversible upon re-addition of the solvent. Our data illuminate a previously unnoted secondary structural plasticity of the Aβ peptide in amyloid oligomers that could bear relevance for Aβ's interactions with cellular structures of low polarity. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular Biology 05/2015; DOI:10.1016/j.jmb.2015.05.002 · 4.33 Impact Factor
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    ABSTRACT: Amyloid β (Aβ) fibrils are strongly involved in the pathogenesis of Alzheimer's diseases. The Aβ oligomers represent a non-fibrillar intermediate state of fibril formation.Here we explored the potential of Aβ peptide oligomers as a novel class of biological nanoparticles for macrophage targeting. This study shows that Aβ(1-40) peptide oligomers have a near-spheroid shape and due to a β-sheet assembly possess a compact, quasi-crystalline architecture. Additionally, FRET analysis revealed that Aβ(1-40) are structurally dynamic. Hence, they represent highly structured and biocompatible nanoparticles, which can be readily degraded by natural enzymes. Macrophages play a major role in immunity and tissue repair. However, recent evidence implicates them in progression of atherosclerosis, fibrosis, tumor initiation and development. In this context, specific labeling and imaging of macrophages are of special interest for diagnostic and therapeutic applications. We found that oligomeric Aβ(1-40) is preferentially taken up by macrophages compared to peripheral mononuclear cells. This prompted us to conjugate oligomeric Aβ(1-40) to nanoparticles composed of a superparamagnetic iron oxide (SPIO) core and a polymeric shell used to increase contrast in magnetic resonance imaging (MRI). Such functionalization enabled the preferential uptake of SPIO-Aβ contrast agents by macrophages. Thus, functionalization with Aβ oligomers might be used to diagnose disease-associated macrophage accumulation by MRI.
    The FASEB Journal 04/2015; 29(April 2015):577.5. · 5.04 Impact Factor
  • Dietmar Rudolf Thal · Marcus Fändrich ·

    Acta Neuropathologica 01/2015; 129(2). DOI:10.1007/s00401-015-1387-2 · 10.76 Impact Factor
  • Magdalena Bereza · Marcus Faendrich ·
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    ABSTRACT: Alzheimer’s disease characteristically involves the deposition of Aβ peptide as fibril-containing amyloid plaques. Examination of Aβ amyloid fibrils formed in vitro revealed a profound structural polymorphism of the filaments. The structure of polymorphic Aβ fibrils has been investigated with cryoelectron microscopy or nuclear magnetic resonance spectroscopy. This research revealed the common protofilament substructure of Aβ fibril morphologies. However, there are also significant differences in the structural models of fibrillar Aβ peptide that have been put forward by the different experimental techniques. X-ray crystallography of peptide fragments derived from Aβ peptide further illuminated the structural variability of the cross-β conformations adopted. This chapter provides a general overview of the data on polymorphism in Aβ fibrils, and presents current concepts to classify and to rationalize this phenomenon. As evidence suggests that polymorphism of Aβ fibril structures occurs in vivo, possible biologic consequences of this phenomenon are discussed.
    Bio-nanoimaging, Edited by Vladimir N. Uversky, Yuri L. Lyubchenko, 12/2014: chapter 17: pages 189-196; Academic Press., ISBN: 978-0-12-394431-3
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    ABSTRACT: Amyloid deposits are common in various tissues as a consequence of misfolded proteins. However, secretory protein and peptides are often stored in membrane coated granules as functional amyloids. In this article, we present a detailed characterization of in vitro generated amyloid fibrils from human parathyroid hormone (hPTH(1-84)). Fully mature fibrils could be obtained after a short lag phase within less than one hour at 65°C. These fibrils showed all characteristic of a cross-β structure. Protease cleavage combined with mass spectrometry identified the central region of the peptide hormone involved in the fibril core formation. EGCG, an inhibitor of amyloid fibril formation, showed binding to residues in the peptide monomers corresponding to the later fibril core and thus explaining the inhibition of the fibril growth. Conformational and dynamic studies by solid-state NMR further corroborated the cross-β core of the fibrils, but also identified highly mobile segments with random coil structure not belonging to the rigid fibril core. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 12/2014; 1854(4). DOI:10.1016/j.bbapap.2014.12.020 · 2.75 Impact Factor
  • Dietmar Rudolf Thal · Jochen Walter · Takaomi C Saido · Marcus Fändrich ·
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    ABSTRACT: Alzheimer's disease (AD) is characterized by β-amyloid plaques and intraneuronal τ aggregation usually associated with cerebral amyloid angiopathy (CAA). Both β-amyloid plaques and CAA deposits contain fibrillar aggregates of the amyloid β-peptide (Aβ). Aβ plaques and CAA develop first in neocortical areas of preclinical AD patients and, then, expand in a characteristic sequence into further brain regions with end-stage pathology in symptomatic AD patients. Aβ aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque- and non-CAA-associated Aβ aggregates have been described. Amyloid fibrils are products of a complex self-assembly process that involves different types of transient intermediates. Amongst these intermediate species are protofibrils and oligomers. Different variants of Aβ peptides may result from alternative processing or from mutations that lead to rare forms of familial AD. These variants can exhibit different self-assembly and aggregation properties. In addition, several post-translational modifications of Aβ have been described that result, for example, in the production of N-terminal truncated Aβ with pyroglutamate modification at position 3 (AβN3pE) or of Aβ phosphorylated at serine 8 (pSer8Aβ). Both AβN3pE and pSer8Aβ show enhanced aggregation into oligomers and fibrils. However, the earliest detectable soluble and insoluble Aβ aggregates in the human brain exhibit non-modified Aβ, whereas AβN3pE and pSer8Aβ are detected in later stages. This finding indicates the existence of different biochemical stages of Aβ aggregate maturation with pSer8Aβ being related mainly to cases with symptomatic AD. The conversion from preclinical to symptomatic AD could thereby be related to combined effects of increased Aβ concentration, maturation of aggregates and spread of deposits into additional brain regions. Thus, the inhibition of Aβ aggregation and maturation before entering the symptomatic stage of the disease as indicated by the accumulation of pSer8Aβ may represent an attractive treatment strategy for preventing disease progression.
    Acta Neuropathologica 12/2014; 129(2). DOI:10.1007/s00401-014-1375-y · 10.76 Impact Factor
  • Gunilla T Westermark · Marcus Fändrich · Per Westermark ·
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    ABSTRACT: The understanding of why and how proteins misfold and aggregate into amyloid fibrils has increased considerably during recent years. Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation. Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules. In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood. Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease. This review summarizes current knowledge about AA amyloidosis. The systemic amyloidoses have been regarded as intractable conditions, but improvements in the understanding of fibril composition and pathogenesis over the past decade have led to the development of a number of different therapeutic approaches with promising results. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 10 is January 24, 2015. Please see for revised estimates.
    Annual Review of Pathology Mechanisms of Disease 10/2014; 10(1). DOI:10.1146/annurev-pathol-020712-163913 · 18.75 Impact Factor
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    ABSTRACT: Amyloid oligomers are nonfibrillar polypeptide aggregates linked to diseases, such as Alzheimer's and Parkinson's. Here we show that these aggregates possess a compact, quasi-crystalline architecture that presents significant nanoscale regularity. The amyloid oligomers are dynamic assemblies and are able to release their individual subunits. The small oligomeric size and spheroid shape confer diffusible characteristics, electrophoretic mobility, and the ability to enter hydrated gel matrices or cells. We finally showed that the amyloid oligomers can be labeled with both fluorescence agents and iron oxide nanoparticles and can target macrophage cells. Oligomer amyloids may provide a new biological nanomaterial for improved targeting, drug release, and medical imaging.
    ACS Nano 10/2014; 8(11). DOI:10.1021/nn503960h · 12.88 Impact Factor
  • Christian Haupt · Marcus Fändrich ·
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    ABSTRACT: The aberrant self-assembly of polypeptide chains into amyloid structures is a common phenomenon in several neurodegenerative diseases, systemic amyloidosis, and ‘normal’ aging. Improvements in laboratory-scale detection of these structures, their clinical diagnosis, and the treatment of disease likely depend on the advent of new molecules that recognize particular states or induce their clearance in vivo. This review will describe what biotechnology can do to generate proteinaceous amyloid-binders, explain their molecular recognition mechanisms, and summarize possibilities to functionalize further these ligands for specific applications.
    Trends in Biotechnology 10/2014; 32(10). DOI:10.1016/j.tibtech.2014.08.004 · 11.96 Impact Factor
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    ABSTRACT: Unlabelled: Semen enhances HIV infection in vitro, but how long it retains this activity has not been carefully examined. Immediately postejaculation, semen exists as a semisolid coagulum, which then converts to a more liquid form in a process termed liquefaction. We demonstrate that early during liquefaction, semen exhibits maximal HIV-enhancing activity that gradually declines upon further incubation. The decline in HIV-enhancing activity parallels the degradation of peptide fragments derived from the semenogelins (SEMs), the major components of the coagulum that are cleaved in a site-specific and progressive manner upon initiation of liquefaction. Because amyloid fibrils generated from SEM fragments were recently demonstrated to enhance HIV infection, we set out to determine whether any of the liquefaction-generated SEM fragments associate with the presence of HIV-enhancing activity. We identify SEM1 from amino acids 86 to 107 [SEM1(86-107)] to be a short, cationic, amyloidogenic SEM peptide that is generated early in the process of liquefaction but that, conversely, is lost during prolonged liquefaction due to the activity of serine proteases. Synthetic SEM1(86-107) amyloids directly bind HIV-1 virions and are sufficient to enhance HIV infection of permissive cells. Furthermore, endogenous seminal levels of SEM1(86-107) correlate with donor-dependent variations in viral enhancement activity, and antibodies generated against SEM1(86-107) recognize endogenous amyloids in human semen. The amyloidogenic potential of SEM1(86-107) and its virus-enhancing properties are conserved among great apes, suggesting an evolutionarily conserved function. These studies identify SEM1(86-107) to be a key, HIV-enhancing amyloid species in human semen and underscore the dynamic nature of semen's HIV-enhancing activity. Importance: Semen, the most common vehicle for HIV transmission, enhances HIV infection in vitro, but how long it retains this activity has not been investigated. Semen naturally undergoes physiological changes over time, whereby it converts from a gel-like consistency to a more liquid form. This process, termed liquefaction, is characterized at the molecular level by site-specific and progressive cleavage of SEMs, the major components of the coagulum, by seminal proteases. We demonstrate that the HIV-enhancing activity of semen gradually decreases over the course of extended liquefaction and identify a naturally occurring semenogelin-derived fragment, SEM1(86-107), whose levels correlate with virus-enhancing activity over the course of liquefaction. SEM1(86-107) amyloids are naturally present in semen, and synthetic SEM1(86-107) fibrils bind virions and are sufficient to enhance HIV infection. Therefore, by characterizing dynamic changes in the HIV-enhancing activity of semen during extended liquefaction, we identified SEM1(86-107) to be a key virus-enhancing component of human semen.
    Journal of Virology 04/2014; 88(13). DOI:10.1128/JVI.00269-14 · 4.44 Impact Factor
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    ABSTRACT: The self-assembly of Abeta peptides into a range of conformationally heterogeneous amyloid states represents a fundamental event in Alzheimer's disease. Within these structures oligomeric intermediates are considered to be particularly pathogenic. To test this hypothesis we have used a conformational targeting approach where particular conformational states, such as oligomers or fibrils, are recognized in vivo by state-specific antibody fragments. We show that oligomer targeting with the KW1 antibody fragment, but not fibril targeting with the B10 antibody fragment, affects toxicity in Abeta-expressing Drosophila melanogaster. The effect of KW1 is observed to occur selectively with flies expressing Abeta(1-40) and not with those expressing Abeta(1-42) or the arctic variant of Abeta(1-42) This finding is consistent with the binding preference of KW1 for Abeta(1-40) oligomers that has been established in vitro. Strikingly, and in contrast to the previously demonstrated in vitro ability of this antibody fragment to block oligomeric toxicity in long-term potentiation measurements, KW1 promotes toxicity in the flies rather than preventing it. This result shows the crucial importance of the environment in determining the influence of antibody binding on the nature and consequences of the protein misfolding and aggregation. While our data support to the pathological relevance of oligomers, they highlight the issues to be addressed when developing inhibitory strategies that aim to neutralize these states by means of antagonistic binding agents.
    04/2014; 2(1):43. DOI:10.1186/2051-5960-2-43
  • Tobias Aumüller · Marcus Fändrich ·
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    ABSTRACT: Amyloid fibrils are formed from polypeptide chains assembled into an organized fibrillar structure. Now, it has been shown that such fibrillar structures can also bind metal ions and catalyse chemical reactions.
    Nature Chemistry 03/2014; 6(4):273-4. DOI:10.1038/nchem.1904 · 25.33 Impact Factor
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    ABSTRACT: Naturally occurring fragments of the abundant semen proteins prostatic acid phosphatase (PAP) and semenogelins form amyloid fibrils in vitro. These fibrils boost HIV infection and may play a key role in the spread of the AIDS pandemic. However, the presence of amyloid fibrils in semen remained to be demonstrated. Here, we use state of the art confocal and electron microscopy techniques for direct imaging of amyloid fibrils in human ejaculates. We detect amyloid aggregates in all semen samples and find that they partially consist of PAP fragments, interact with HIV particles and increase viral infectivity. Our results establish semen as a body fluid that naturally contains amyloid fibrils that are exploited by HIV to promote its sexual transmission.
    Nature Communications 02/2014; 5:3508. DOI:10.1038/ncomms4508 · 11.47 Impact Factor
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    ABSTRACT: Alzheimer's disease is characterized by the deposition of amyloid-β peptide in the brain. N-terminal truncation resulting in the formation of AβN3pE and phosphorylation at serine 8 have been reported to modify aggregation properties of amyloid-β. Biochemically, soluble, dispersible, membrane-associated, and insoluble, plaque-associated amyloid-β aggregates have been distinguished. Soluble and dispersible amyloid-β aggregates are both in mixture with the extracellular or intracellular fluid but dispersible aggregates can be cleared from proteins in solution by ultracentrifugation. To clarify the role of phosphorylated amyloid-β and AβN3pE in soluble, dispersible, membrane-associated, and plaque-associated amyloid-β aggregates in the pathogenesis of Alzheimer's disease we studied brains from 21 cases with symptomatic Alzheimer's disease, 33 pathologically preclinical Alzheimer's disease cases, and 20 control cases. Western blot analysis showed that soluble, dispersible, membrane-associated and plaque-associated amyloid-β aggregates in the earliest preclinical stage of Alzheimer's disease did not exhibit detectable amounts of AβN3pE and phosphorylated amyloid-β. This stage was referred to as biochemical stage 1 of amyloid-β aggregation and accumulation. In biochemical amyloid-β stage 2, AβN3pE was additionally found whereas phosphorylated amyloid-β was restricted to biochemical amyloid-β stage 3, the last stage of amyloid-β aggregation. Phosphorylated amyloid-β was seen in the dispersible, membrane-associated, and plaque-associated fraction. All cases with symptomatic Alzheimer's disease in our sample fulfilled biochemical amyloid-β stage 3 criteria, i.e. detection of phosphorylated amyloid-β. Most, but not all, cases with pathologically preclinical Alzheimer's disease had biochemical amyloid-β stages 1 or 2. Immunohistochemistry confirmed the hierarchical occurrence of amyloid-β, AβN3pE, and phosphorylated amyloid-β in amyloid plaques. Phosphorylated amyloid-β containing plaques were, thereby, seen in all symptomatic cases with Alzheimer's disease but only in a few non-demented control subjects. The biochemical amyloid-β stages correlated with the expansion of amyloid-β plaque deposition and with that of neurofibrillary tangle pathology. Taken together, we demonstrate that AβN3pE and phosphorylated amyloid-β are not only detectable in plaques, but also in soluble and dispersible amyloid-β aggregates outside of plaques. They occur in a hierarchical sequence that allows the distinction of three stages. In light of our findings, it is tempting to speculate that this hierarchical, biochemical sequence of amyloid-β aggregation and accumulation is related to disease progression and may be relevant for an increasing toxicity of amyloid-β aggregates.
    Brain 02/2014; 137(3). DOI:10.1093/brain/awt362 · 9.20 Impact Factor

  • Neurology Psychiatry and Brain Research 02/2014; 20(1):24–25. DOI:10.1016/j.npbr.2014.01.173 · 0.10 Impact Factor
  • Christian Haupt · Dietmar Rudolf Thal · Uwe Horn · Marcus Fändrich ·
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    ABSTRACT: Conformational diseases, such as Alzheimer’s or Parkinson’s, are characterized by the misfolding of endogenous polypeptide chains into abnormal amyloid fibril conformations. To better analyze this process and its biological consequences and to generate tools for targeted interference in vitro and in vivo, we have biotechnologically generated a set of antibody fragments that are able to discriminate by binding between different amyloid assembly states.
    BioSpektrum 02/2014; 20(1-1):12-14. DOI:10.1007/s12268-014-0397-2
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    ABSTRACT: This chapter contains sections titled: Detection of Fibrillar Polymorphism The Structural Definition of Fibril Polymorphism The Two Classes of Fibril Polymorphism How Does Fibrillar Polymorphism Arise? The Interconversion of Fibril Polymorphs The Biological Implications of Fibril Polymorphism Summary Acknowledgments References
    Amyloid Fibrils and Prefibrillar Aggregates, 01/2013: pages 321-343; , ISBN: 9783527332007
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    ABSTRACT: Oligomers are intermediates of the β-amyloid (Aβ) peptide fibrillogenic pathway and are putative pathogenic culprits in Alzheimer's disease (AD). Here we report the biotechnological generation and biochemical characterization of an oligomer-specific antibody fragment, KW1. KW1 not only discriminates between oligomers and other Aβ conformations, such as fibrils or disaggregated peptide; it also differentiates between different types of Aβ oligomers, such as those formed by Aβ (1-40) and Aβ (1-42) peptide. This high selectivity of binding contrasts sharply with many other conformational antibodies that interact with a large number of structurally analogous but sequentially different antigens. X-ray crystallography, NMR spectroscopy, and peptide array measurements imply that KW1 recognizes oligomers through a hydrophobic and significantly aromatic surface motif that includes Aβ residues 18-20. KW1-positive oligomers occur in human AD brain samples and induce synaptic dysfunctions in living brain tissues. Bivalent KW1 potently neutralizes this effect and interferes with Aβ assembly. By altering a specific step of the fibrillogenic cascade, it prevents the formation of mature Aβ fibrils and induces the accumulation of nonfibrillar aggregates. Our data illuminate significant mechanistic differences in oligomeric and fibril recognition and suggest the considerable potential of KW1 in future studies to detect or inhibit specific types of Aβ conformers.
    Proceedings of the National Academy of Sciences 07/2012; 109(31):12503-8. DOI:10.1073/pnas.1206433109 · 9.67 Impact Factor

Publication Stats

4k Citations
495.08 Total Impact Points


  • 2014-2015
    • Universität Ulm
      • Institute of Pathology
      Ulm, Baden-Württemberg, Germany
  • 2011-2012
    • Max-Planck-Forschungsstelle für Enzymologie der Proteinfaltung
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2008-2012
    • Martin Luther University of Halle-Wittenberg
      • Institute of Biochemistry and Biotechnology
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2006-2010
    • Leibniz Institute for Age Research - Fritz Lipmann Institute
      Jena, Thuringia, Germany
  • 2004
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 2001
    • University of Oxford
      • Chemical Research Laboratory
      Oxford, ENG, United Kingdom