Marcus Fändrich

Universität Ulm, Ulm, Baden-Württemberg, Germany

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Publications (74)391.25 Total impact

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    ABSTRACT: Semen enhances HIV infection in vitro, but how long it retains this activity has not been carefully examined. Immediately post-ejaculation semen exists as a semi-solid 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 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(86-107) as a short, cationic, amyloidogenic SEM peptide that is generated early in the process of liquefaction, but 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 amongst great apes, suggesting an evolutionarily conserved function. These studies identify SEM1(86-107) as a key, HIV-enhancing amyloid species in human semen, and underscore the dynamic nature of semen's HIV-enhancing activity. 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 viral 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) as a key viral-enhancing component of human semen.
    Journal of Virology 04/2014; · 5.08 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.
    Acta neuropathologica communications. 04/2014; 2(1):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. · 21.76 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. · 10.74 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; · 10.23 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. 01/2014;
  • Neurology Psychiatry and Brain Research 01/2014; 20(1):24–25. · 0.13 Impact Factor
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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. · 9.81 Impact Factor
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    ABSTRACT: Two-faced culprit: Fibrils of recombinantly produced amyloid β peptides (Aβs; residues 1-40) gave well-resolved solid-state NMR spectra. Two sets of resonances corresponding to residues 12-40 and 21-38 of the Aβ primary sequence were observed. Statistical analysis of electron microscopy data revealed that it was composed of a single Aβ polymorph, thus indicating that this Aβ fibril is composed of an asymmetric dimer.
    Angewandte Chemie International Edition 05/2012; 51(25):6136-9. · 11.34 Impact Factor
  • Neurology Psychiatry and Brain Research 03/2012; 18(2):93. · 0.13 Impact Factor
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    ABSTRACT: Learn about Alzheimer: The molecular conformation of a toxic β-amyloid oligomer structure was determined by NMR spectroscopy. The measurements show a N-terminal β strand that controls the partitioning between oligomer and protofibril formation. Targeting the N-terminus of the peptide neutralizes Aβ-dependent neuronal dysfunctions. The data have important implications for understanding the structural basis of Alzheimer's disease.
    Angewandte Chemie International Edition 02/2012; 51(7):1576-9. · 11.34 Impact Factor
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    ABSTRACT: Soluble amyloid β-protein (Aβ) aggregates have been identified in the Alzheimer's disease (AD) brain. Dispersed Aβ aggregates in the brain parenchyma are different from soluble, membrane-associated and plaque-associated solid aggregates. They are in mixture with the extra- or intracellular fluid but can be separated from soluble proteins by ultracentrifugation. To clarify the role of dispersible Aβ aggregates for neurodegeneration we analyzed 2 different amyloid precursor protein (APP)-transgenic mouse models. APP23 mice overexpress human mutant APP with the Swedish mutation. APP51/16 mice express high levels of human wild type APP. Both mice develop Aβ-plaques. Dendritic degeneration, neuron loss, and loss of asymmetric synapses were seen in APP23 but not in APP51/16 mice. The soluble and dispersible fractions not separated from one another were received as supernatant after centrifugation of native forebrain homogenates at 14,000 × g. Subsequent ultracentrifugation separated the soluble, i.e., the supernatant, from the dispersible fraction, i.e., the resuspended pellet. The major biochemical difference between APP23 and APP51/16 mice was that APP23 mice exhibited higher levels of dispersible Aβ oligomers, protofibrils and fibrils precipitated with oligomer (A11) and protofibril/fibril (B10AP) specific antibodies than APP51/16 mice. These differences, rather than soluble Aβ and Aβ plaque pathology were associated with dendritic degeneration, neuron, and synapse loss in APP23 mice in comparison with APP51/16 mice. Immunoprecipitation of dispersible Aβ oligomers, protofibrils, and fibrils revealed that they were associated with APP C-terminal fragments (APP-CTFs). These results indicate that dispersible Aβ oligomers, protofibrils, and fibrils represent an important pool of Aβ aggregates in the brain that critically interact with membrane-associated APP C-terminal fragments. The concentration of dispersible Aβ aggregates, thereby, presumably determines its toxicity.
    Neurobiology of aging 02/2012; 33(11):2641-60. · 5.94 Impact Factor
  • Marcus Fändrich
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    ABSTRACT: Oligomeric intermediates are non-fibrillar polypeptide assemblies that occur during amyloid fibril formation and that are thought to underlie the aetiology of amyloid diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Focusing primarily on the oligomeric states formed from Alzheimer's disease β-amyloid (Aβ) peptide, this review will make references to other polypeptide systems, highlighting common principles or sequence-specific differences. The covered topics include the structural properties and polymorphism of oligomers, the biophysical mechanism of peptide self-assembly and its role for pathogenicity in amyloid disease. Oligomer-dependent toxicity mechanisms will be explained along with recently emerging possibilities of interference.
    Journal of Molecular Biology 01/2012; 421(4-5):427-40. · 3.91 Impact Factor
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    ABSTRACT: Several studies indicate that NMDA receptor signaling is involved in Aβ oligomer-mediated impairment of neuronal function and morphology. Utilizing primary neuronal cell culture and hippocampal slices from rat and mouse, we found that Aβ oligomer administration readily impairs long-term potentiation, reduces baseline synaptic transmission, decreases neuronal spontaneous network activity and induces retraction of synaptic contacts long before major cytotoxic effects are visible. Interestingly, all these effects can be blocked with the NR2B-containing NMDA-receptor antagonist ifenprodil or Ro 25-6981 suggesting that activation of downstream effectors of these receptors is involved in early detrimental actions of Aβ oligomers. In line we found that Jacob, a messenger that can couple extrasynaptic NMDA-receptor activity to CREB dephosphorylation, accumulates in the nucleus after Aβ oligomer administration and that the nuclear accumulation of Jacob can be blocked by a simultaneous application of ifenprodil. We conclude that Aβ oligomers induce early neuronal dysfunction mainly by activation of NR2B-containing NMDA-receptors.
    Neurobiology of aging 12/2011; 32(12):2219-28. · 5.94 Impact Factor
  • Isabel Morgado, Marcus Fändrich
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    ABSTRACT: The self-assembly of β-amyloid (Aβ) peptide into highly ordered amyloid fibril structures represents one of the pathological hallmarks of Alzheimer's disease. This process leads to the transient stabilization of ordered or disordered intermediates, which are thought to act as the main pathogenic culprits in neurodegenerative amyloid disease. This review describes recent results from different biophysical techniques, ranging from structure determination to single-particle methods by which the outgrowth of individual fibrils can be followed, and it explains their contributions towards understanding the mechanism of assembly. Finally, we will outline emerging methods and molecules to specifically interfere with the assembly and pathogenic impact of Aβ peptide.
    Current Opinion in Colloid & Interface Science - CURR OPIN COLLOID INTERFACE S. 12/2011;
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    ABSTRACT: Several lines of evidence indicate that prefibrillar assemblies of amyloid-β (Aβ) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Aβ fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aβ peptides and stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Aβ oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Aβ oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.
    Nature Chemical Biology 11/2011; 8(1):93-101. · 12.95 Impact Factor
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    ABSTRACT: The oligomerization of Aβ peptide into amyloid fibrils is a hallmark of Alzheimer's disease. Due to its biological relevance, phosphate is the most commonly used buffer system for studying the formation of Aβ and other amyloid fibrils. Investigation into the characteristics and formation of amyloid fibrils frequently relies upon material formed in vitro, predominantly in phosphate buffers. Herein, we examine the effects on the fibrillation and oligomerization mechanism of Aβ peptide that occur due solely to the influence of phosphate buffer. We reveal that significant differences in amyloid fibrillation are observed due to fibrillation being initiated in phosphate or HEPES buffer (at physiological pH and temperature). Except for the differing buffer ions, all experimental parameters were kept constant. Fibril formation was assessed using fluorescently monitored kinetic studies, microscopy, X-ray fiber diffraction and infrared and nuclear magnetic resonance spectroscopies. Based on this set up, we herein reveal profound effects on the mechanism and speed of Aβ fibrillation. The three histidine residues at positions 6, 13 and 14 of Aβ(1-40) are instrumental in these mechanistic changes. We conclude that buffer plays a more significant role in fibril formation than has been generally acknowledged.
    Biochemical and Biophysical Research Communications 06/2011; 409(3):385-8. · 2.28 Impact Factor
  • Angewandte Chemie 03/2011; 123(12).
  • Angewandte Chemie International Edition 03/2011; 50(12):2837-40. · 11.34 Impact Factor

Publication Stats

2k Citations
391.25 Total Impact Points

Institutions

  • 2011–2014
    • Universität Ulm
      • Institute of Pathology
      Ulm, Baden-Württemberg, Germany
    • University of Leipzig
      • Institut für Medizinische Physik und Biophysik
      Leipzig, Saxony, Germany
  • 2009–2012
    • Martin Luther University of Halle-Wittenberg
      • Institute of Biochemistry and Biotechnology
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2008–2012
    • Max-Planck-Forschungsstelle für Enzymologie der Proteinfaltung
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2008–2011
    • Leibniz Institute for Neurobiology
      • Project Group Neuropharmacology
      Magdeburg, Saxony-Anhalt, Germany
  • 2006–2010
    • Leibniz Institute for Age Research - Fritz Lipmann Institute
      Jena, Thuringia, Germany
  • 2008–2009
    • Brandeis University
      Waltham, Massachusetts, United States
  • 2007
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2005
    • Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute
      Jena, Thuringia, Germany
  • 2004
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 2000–2002
    • University of Oxford
      • Chemical Research Laboratory
      Oxford, England, United Kingdom