Louise C Serpell

University of Sussex, Brighton, England, United Kingdom

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Publications (128)744.54 Total impact

  • Rebecca E. Joyce · Thomas L. Williams · Louise C. Serpell · Iain J. Day
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    ABSTRACT: Phospholipid vesicles are commonly used as biomimetics in the investigation of the interaction of various species with cell membranes. In this paper we present a 31P NMR investigation of a simple vesicle system using a paramagnetic shift reagent to probe the inner and outer layers of the lipid bilayer. Time-dependent changes in the 31P NMR signal are observed, which differ whether the paramagnetic species is inside or outside the vesicle, and on the choice of buffer solution used. An interpretation of these results is given in terms of the interaction of the paramagnetic shift reagent with the lipids.
    No preview · Article · Feb 2016 · Chemical Physics Letters
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    Mahmoud Bukar Maina · Youssra K Al-Hilaly · Louise C Serpell
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    ABSTRACT: Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer's disease (AD). For nearly four decades, research efforts have focused more on tau's role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau's localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration.
    Preview · Article · Jan 2016
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    Thomas L Williams · Louise C Serpell · Brigita Urbanc
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    ABSTRACT: Oligomeric assemblies are postulated to be proximate neurotoxic species in human diseases associated with aberrant protein aggregation. Their heterogeneous and transient nature makes their structural characterization difficult. Size distributions of oligomers of several amyloidogenic proteins, including amyloid β-protein (Aβ) relevant to Alzheimer's disease (AD), have been previously characterized in vitro by photo-induced cross-linking of unmodified proteins (PICUP) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Due to non-physiological conditions associated with the PICUP chemistry, Aβ oligomers cross-linked by PICUP may not be representative of in vivo conditions. Here, we examine an alternative Copper and Hydrogen peroxide Induced Cross-linking of Unmodified Proteins (CHICUP), which utilizes naturally occurring divalent copper ions and hydrogen peroxide and does not require photo activation. Our results demonstrate that CHICUP and PICUP applied to the two predominant Aβ alloforms, Aβ40 and Aβ42, result in similar oligomer size distributions. Thioflavin T fluorescence data and atomic force microscopy images demonstrate that both CHICUP and PICUP stabilize Aβ oligomers and attenuate fibril formation. Relative to noncross-linked peptides, CHICUP-treated Aβ40 and Aβ42 cause prolonged disruption to biomimetic lipid vesicles. CHICUP-stabilized Aβ oligomers link the amyloid cascade, metal, and oxidative stress hypotheses of AD into a more comprehensive understanding of the molecular basis of AD pathology. Because copper and hydrogen peroxide are elevated in the AD brain, CHICUP-stabilized Aβ oligomers are biologically relevant and should be further explored as a new therapeutic target.
    Full-text · Article · Dec 2015 · Biochimica et Biophysica Acta
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    ABSTRACT: Soluble Amyloid-beta (Aβ) oligomers are a source of cytotoxicity in Alzheimer's disease (AD). The toxicity of Aβ oligomers may arise from their ability to interact with and disrupt cellular membranes mediated by GM1 ganglioside receptors within these membranes. Therefore, inhibition of Aβ-membrane interactions could provide a means of preventing the toxicity associated with Aβ. Here, using Surface Plasmon field-enhanced Fluorescence Spectroscopy, we determine that the lanthanide, Europium III chloride (Eu(3+)), strongly binds to GM1 ganglioside-containing membranes and prevents the interaction with Aβ42 leading to a loss of the peptides ability to cause membrane permeation. Here we discuss the molecular mechanism by which Eu(3+) inhibits Aβ42-membrane interactions and this may lead to protection of membrane integrity against Aβ42 induced toxicity.
    Full-text · Article · Oct 2015 · FEBS letters
  • Zahraa S Al-Garawi · Julian R Thorpe · Louise C Serpell
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    ABSTRACT: Many peptides self-assemble to form amyloid fibrils. We previously explored the sequence propensity to form amyloid using variants of a designed peptide with sequence KFFEAAAKKFFE. These variant peptides form highly stable amyloid fibrils with varied lateral assembly and are ideal to template further assembly of non-proteinaceous material. Herein, we show that the fibrils formed by peptide variants can be coated with a layer of silica to produce silica nanowires using tetraethyl-orthosilicate. The resulting nanowires were characterized using electron microscopy (TEM), X-ray fiber diffraction, FTIR and cross-section EM to reveal a nanostructure with peptidic core. Lysine residues play a role in templating the formation of silica on the fibril surface and, using this library of peptides, we have explored the contributions of lysine as well as arginine to silica templating, and find that sequence plays an important role in determining the physical nature and structure of the resulting nanowires.
    No preview · Article · Oct 2015 · Angewandte Chemie International Edition
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    ABSTRACT: An ability to design peptide-based nanotubes (PNTs) rationally with defined and mutable internal channels would advance understanding of peptide self-assembly, and present new biomaterials for nanotechnology and medicine. PNTs have been made from Fmoc dipeptides, cyclic peptides, and lock-washer helical bundles. Here we show that blunt-ended α-helical barrels-i.e., pre-assembled bundles of α-helices with central channels-can be used as building blocks for PNTs. This approach is general and systematic, and uses a set of de novo helical bundles as standards. One of these bundles, a hexameric α-helical barrel, assembles into highly ordered PNTs, for which we have determined a structure by combining cryo-transmission electron microscopy, X-ray fiber diffraction and model building. The structure reveals that the overall symmetry of the peptide module plays a critical role in ripening and ordering of the supramolecular assembly. PNTs based on pentameric, hexameric and heptameric α-helical barrels sequester hydrophobic dye within their lumens.
    No preview · Article · Jul 2015 · Journal of the American Chemical Society
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    Full-text · Dataset · Jul 2015
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    ABSTRACT: Most Alzheimer’s disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development of early-onset familial AD. This type of AD is associated with a younger age at disease onset, increased β-amyloid accumulation, and Aβ deposition in cerebral blood vessel walls, giving rise to cerebral amyloid angiopathy (CAA). It remains largely unknown how the Italian mutation results in the clinical phenotype that is characteristic of CAA. We therefore investigated how this single point mutation may affect the aggregation of Aβ1–42 in vitro and structurally characterized the resulting fibrils using a biophysical approach. This paper reports that wild-type and Italian-mutant Aβ both form fibrils characterized by the cross-β architecture, but with distinct β-sheet organizations, resulting in differences in thioflavin T fluorescence and solvent accessibility. E22K Aβ1–42 oligomers and fibrils both display an antiparallel β-sheet structure, in comparison with the parallel β-sheet structure of wild-type fibrils, characteristic of most amyloid fibrils described in the literature. Moreover, we demonstrate structural plasticity for Italian-mutant Aβ fibrils in a pH-dependent manner, in terms of their underlying β-sheet arrangement. These findings are of interest in the ongoing debate that (1) antiparallel β-sheet structure might represent a signature for toxicity, which could explain the higher toxicity reported for the Italian mutant, and that (2) fibril polymorphism might underlie differences in disease pathology and clinical manifestation. Electronic supplementary material The online version of this article (doi:10.1007/s00018-015-1983-2) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jul 2015 · Cellular and Molecular Life Sciences CMLS
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    J A Ratnayaka · L C Serpell · A J Lotery
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    ABSTRACT: Age-related macular degeneration (AMD) is one of the most common causes of irreversible blindness affecting nearly 50 million individuals globally. The disease is characterised by progressive loss of central vision, which has significant implications for quality of life concerns in an increasingly ageing population. AMD pathology manifests in the macula, a specialised region of the retina, which is responsible for central vision and perception of fine details. The underlying pathology of this complex degenerative disease is incompletely understood but includes both genetic as well as epigenetic risk factors. The recent discovery that amyloid beta (Aβ), a highly toxic and aggregate-prone family of peptides, is elevated in the ageing retina and is associated with AMD has opened up new perspectives on the aetiology of this debilitating blinding disease. Multiple studies now link Aβ with key stages of AMD progression, which is both exciting and potentially insightful, as this identifies a well-established toxic agent that aggressively targets cells in degenerative brains. Here, we review the most recent findings supporting the hypothesis that Aβ may be a key factor in AMD pathology. We describe how multiple Aβ reservoirs, now reported in the ageing eye, may target the cellular physiology of the retina as well as associated layers, and propose a mechanistic pathway of Aβ-mediated degenerative change leading to AMD.Eye advance online publication, 19 June 2015; doi:10.1038/eye.2015.100.
    Preview · Article · Jun 2015 · Eye (London, England)
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    ABSTRACT: A number of Fmoc amino acids can be effective low molecular weight hydrogelators. The type of gel formed depends on the amino acid used and, in the case of FmocF, the final pH of the system. The single crystal structure of two of the gelators (FmocF and FmocY) have been solved and the data compared to the fibre X-ray diffraction data. FmocF, which forms metastable gels, crystallises easily and the data for the fibre phase and crystal phase are relatively similar. The fibre axis in b is consistent with the hydrogen bonding repeat distances and the diffraction pattern calculated from the single crystal structure is a good match with the experimental fibre X-ray diffraction data. On the other hand, there are significant differences between the crystal phase and the fibre phase for FmocY. The packing of FmocY within the crystal structure is created by interactions between the planar Fmoc groups, whilst it is clear that hydrogen bonding drives the self-assembly into fibrillar structures within the gels. This shows that understanding the packing in gel phase by analogy to isolated crystal structures has the potential to lead to erroneous conclusions.
    Full-text · Article · Jun 2015 · CrystEngComm
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    ABSTRACT: Amyloid beta (Aβ) induced neuronal death has been linked to memory loss, perhaps the most devastating symptom of Alzheimer’s disease (AD). Although Aβ-induced impairment of synaptic or intrinsic plasticity is known to occur before any cell death, the links between these neurophysiological changes and the loss of specific types of behavioral memory are not fully understood. Here we used a behaviorally and physiologically tractable animal model to investigate Aβ-induced memory loss and electrophysiological changes in the absence of neuronal death in a defined network underlying associative memory. We found similar behavioral but different neurophysiological effects for Aβ 25-35 and Aβ 1-42 in the feeding circuitry of the snail Lymnaea stagnalis. Importantly, we also established that both the behavioral and neuronal effects were dependent upon the animals having been classically conditioned prior to treatment, since Aβ application before training caused neither memory impairment nor underlying neu
    Full-text · Article · May 2015
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    ABSTRACT: Amyloid beta (Aβ) induced neuronal death has been linked to memory loss, perhaps the most devastating symptom of Alzheimer's disease (AD). Although Aβ-induced impairment of synaptic or intrinsic plasticity is known to occur before any cell death, the links between these neurophysiological changes and the loss of specific types of behavioral memory are not fully understood. Here we used a behaviorally and physiologically tractable animal model to investigate Aβ-induced memory loss and electrophysiological changes in the absence of neuronal death in a defined network underlying associative memory. We found similar behavioral but different neurophysiological effects for Aβ 25-35 and Aβ 1-42 in the feeding circuitry of the snail Lymnaea stagnalis. Importantly, we also established that both the behavioral and neuronal effects were dependent upon the animals having been classically conditioned prior to treatment, since Aβ application before training caused neither memory impairment nor underlying neuronal changes over a comparable period of time following treatment. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the Western world, affecting an estimated 24.3 million individuals globally. AD is characterized by progressive memory loss and the prominent markers are extracellular amyloid plaques, made of amyloid β (Aβ), and intracellular neurofibrillary tangles, composed of hyperphosphorylated tau
    Full-text · Article · May 2015 · Scientific Reports
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    ABSTRACT: Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril of the GNNQQNY peptide fragment of a yeast prion protein. Data from small-angle X-ray solution scattering, fibre diffraction and electron microscopy are combined with existing high-resolution X-ray crystallographic structures to investigate the fibrillation process and the hierarchical fibril structure of the peptide fragment. The elongation of these fibrils proceeds without the accumulation of any detectable amount of intermediate oligomeric species, as is otherwise reported for, for example, glucagon, insulin and α-synuclein. Ribbons constituted of linearly arranged protofilaments are formed. An additional hierarchical layer is generated via the pairing of ribbons during fibril maturation. Based on the complementary data, a quasi-atomic resolution model of the protofilament peptide arrangement is suggested. The peptide structure appears in a β-sheet arrangement reminiscent of the β-zipper structures evident from high-resolution crystal structures, with specific differences in the relative peptide orientation. The complexity of protein fibrillation and structure emphasizes the need to use multiple complementary methods.
    Preview · Article · Apr 2015 · Acta Crystallographica Section D Biological Crystallography
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    ABSTRACT: Accurate prediction of amyloid-forming amino acid sequences remains an important challenge. We here present an online database that provides open access to the largest set of experimentally characterised amyloid forming hexapeptides. To this end, we expanded our previous set of 280 hexapeptides used to develop the Waltz algorithm with 89 peptides from literature review and by systematic experimental characterisation of the aggregation of 720 hexapeptides by transmission electron microscopy (TEM), dye binding and Fourier transform infrared spectroscopy (FTIR). This brings the total number of experimentally characterized hexapeptides in the WALTZ-DB database to 1089, of which 244 are annotated as positive for amyloid formation. Availability and implementation: The WALTZ-DB database is freely available without any registration requirement at http://waltzdb.switchlab.org. frederic.rousseau@switch.vib-kuleuven.be; joost.schymkowitz@switch.vib-kuleuven.be; © The Author (2015). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Jan 2015 · Bioinformatics
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    Kyle L Morris · Lin Chen · Alison Rodger · Dave John Adams · Louise C Serpell
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    ABSTRACT: Low molecular weight hydrogels are formed by molecules that form a matrix that immobilises water to form a self-supporting gel. Such gels have uses as biomaterials such as molecular scaffolds and structures for tissue engineering. One class of low molecular weight gelators (LMWG), naphthalene-conjugated dipeptides, has been shown to form hydrogels via self-assembly following a controlled drop in pH. A library of naphthalene-dipeptides has been generated previously although the relationship between the precursor sequence and the resulting self-assembled structures remained unclear. Here, we have investigated the structural details of a set of dipeptide sequences containing alanine (A) and valine (V) conjugated to naphthalene groups substituted with a Br, CN or H at the 6-position. Electron microscopy, circular dichroism and X-ray fibre diffraction shows that these LMWG may be structurally classified by their composition: the molecular packing is determined by the class of conjugate, whilst the chirality of the self-assemblies can be attributed to the dipeptide sequence. This provides insights into the relationship between the precursor sequence and the macromolecular and molecular structures of the fibres that make up the resulting hydrogels.
    Full-text · Article · Dec 2014 · Soft Matter
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    ABSTRACT: Protein and peptide self-assembly is a powerful design principle for engineering of new biomolecules. More sophisticated biomaterials could be built if both the structure of the overall assembly as well as that of the self-assembling building block could be controlled. To approach this problem we developed a computational design protocol to enable de novo design of self-assembling peptides with predefined structure. The protocol was used to design a peptide building block with a βαβ fold that self-assembles into fibrilar structures. The peptide associates into a double β-sheet structure with tightly packed α-helices decorating the exterior of the fibrils. Using circular dichroism, Fourier transform infrared spectroscopy, electron microscopy and X-ray fiber diffraction we demonstrate that the peptide adopts the designed conformation. The results demonstrate that computational protein design can be used to engineer protein and peptide assemblies with predefined three-dimensional structures, which can serve as scaffolds for the development of functional biomaterials. Rationally designed proteins and peptides could also be used to investigate the subtle energetic and entropic tradeoffs in natural self-assembly processes and the relation between assembly structure and assembly mechanism. We demonstrate that the de novo designed peptide self-assembles with a mechanism that is more complicated than expected, in a process where small changes in solution conditions can lead to significant differences in assembly properties and conformation. These results highlight that formation of structured protein/peptide assemblies is often dependent on the formation of weak but highly precise intermolecular interactions. Copyright © 2014. Published by Elsevier Ltd.
    No preview · Article · Dec 2014 · Journal of Molecular Biology
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    Full-text · Dataset · Dec 2014
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    ABSTRACT: Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties.
    Full-text · Article · Sep 2014 · Nanoscale
  • Louise Serpell
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    ABSTRACT: Amyloid fibrils are formed by numerous proteins and peptides that share little sequence homology. The structures formed are highly ordered and extremely stable, being composed of β-sheet structure and stabilized along their length by hydrogen bonding. The fibrils are formed by several protofilaments that wind around one another in rope-like structures, lending further strength and stability to the resulting fibres. The fact that so many proteins and peptides form amyloid structures under suitable conditions, seems to suggest that the sequence of the precursor is unimportant. However, it is now clear that side chains play a central role in forming interactions between several β-sheets to further stabilize and regulate the structures. The primary sequence plays a central role in determining the rate of fibril formation, the stability of the resulting structure to degradation and the final morphology of the fibrils. The side chains regulate the elongation and growth, and also the lateral association of the protofilament and fibrils, having a significant impact on the final architecture.
    No preview · Article · Aug 2014 · Essays in Biochemistry

  • No preview · Conference Paper · Jul 2014

Publication Stats

9k Citations
744.54 Total Impact Points


  • 2004-2015
    • University of Sussex
      • • School of Life Sciences
      • • Department of Chemistry
      Brighton, England, United Kingdom
  • 2013
    • The University of Warwick
      • Department of Chemistry
      Coventry, England, United Kingdom
  • 1996-2009
    • University of Oxford
      • Laboratory of Molecular Biophysics
      Oxford, ENG, United Kingdom
  • 2008
    • Universität Basel
      • Department of Biophysical Chemistry
      Bâle, Basel-City, Switzerland
  • 2007
    • University of Brighton
      Brighton, England, United Kingdom
  • 2002-2007
    • University of Cambridge
      • • Cambridge Institute for Medical Research
      • • Department of Haematology
      Cambridge, England, United Kingdom
  • 2003
    • University of Bristol
      • School of Physics
      Bristol, ENG, United Kingdom
  • 2001-2002
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
  • 2000
    • The Scripps Research Institute
      • Skaggs Institute for Chemical Biology
      لا هویا, California, United States
  • 1999
    • Medical Research Council (UK)
      • MRC Laboratory of Molecular Biology
      London, ENG, United Kingdom