Louise C Serpell

University of Alabama at Birmingham, Birmingham, Alabama, United States

Are you Louise C Serpell?

Claim your profile

Publications (119)708.59 Total impact

  • Source
  • Source
    [Show abstract] [Hide abstract]
    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.
    Cellular and Molecular Life Sciences CMLS 07/2015; DOI:10.1007/s00018-015-1983-2 · 5.81 Impact Factor
  • Source
    J A Ratnayaka · L C Serpell · A J Lotery
    [Show abstract] [Hide abstract]
    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.
    Eye (London, England) 06/2015; 29(8). DOI:10.1038/eye.2015.100 · 2.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    CrystEngComm 06/2015; DOI:10.1039/C5CE00801H · 4.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
    Scientific Reports 05/2015; 5. DOI:10.1038/srep10614 · 5.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Acta Crystallographica Section D Biological Crystallography 04/2015; 71(Pt 4):882-895. DOI:10.1107/S1399004715001674 · 2.67 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Bioinformatics 01/2015; 31(10). DOI:10.1093/bioinformatics/btv027 · 4.98 Impact Factor
  • Source
    Kyle L Morris · Lin Chen · Alison Rodger · Dave John Adams · Louise C Serpell
    [Show abstract] [Hide abstract]
    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.
    Soft Matter 12/2014; 11(6). DOI:10.1039/C4SM02532F · 4.03 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Journal of Molecular Biology 12/2014; 427(2). DOI:10.1016/j.jmb.2014.12.002 · 4.33 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    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.
    Nanoscale 09/2014; 6(22). DOI:10.1039/C4NR04039B · 7.39 Impact Factor
  • Louise Serpell
    [Show abstract] [Hide abstract]
    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.
    Essays in Biochemistry 08/2014; 56(1):1-10. DOI:10.1042/bse0560001 · 2.84 Impact Factor
  • Source
    Thomas L Williams · Louise C Serpell
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations ("strains") in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.
    Neuron 05/2014; 82(6). DOI:10.1016/j.neuron.2014.04.047 · 15.05 Impact Factor
  • Source
    Karen E Marshall · Ricardo Marchante · Wei-Feng Xue · Louise C Serpell
    [Show abstract] [Hide abstract]
    ABSTRACT: Self-assembly of proteins and peptides into amyloid structures has been the subject of intense and focused research due to their association with neurodegenerative, age-related human diseases and transmissible prion diseases in humans and mammals. Of the disease associated amyloid assemblies, a diverse array of species, ranging from small oligomeric assembly intermediates to fibrillar structures, have been shown to have toxic potential. Equally, a range of species formed by the same disease associated amyloid sequences have been found to be relatively benign under comparable monomer equivalent concentrations and conditions. In recent years, an increasing number of functional amyloids have also been found. These developments show that not all amyloid structures are generically toxic to cells. Given these observations, it is important to understand why amyloid structures may encode such varied toxic potential despite sharing a common core molecular architecture. Here, we discuss possible links between different aspects of amyloidogenic structures and assembly mechanisms with their varied functional effects. We propose testable hypotheses for the relationship between amyloid structure and its toxic potential in the context of recent reports on amyloid sequence, structure, and toxicity relationships.
    Prion 05/2014; 8(2). DOI:10.4161/pri.28860 · 2.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J, et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self-aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the β-turn linking strands C and D caused by loss of the wild-type hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis.
    Proceedings of the National Academy of Sciences 01/2014; 111(4):1539-44. DOI:10.1073/pnas.1317488111 · 9.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Abeta) fibrils. Copper has been implicated to play a role in Alzheimer's disease. Dimers of Abeta have been isolated from AD brain and have been shown to be neurotoxic. We have investigated the formation of dityrosine cross-links in Abeta42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Abetaoligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Abeta in cell cultures treated with oligomeric Abeta42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients. Abeta dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer's disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Abeta and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD.
    12/2013; 1(1):83. DOI:10.1186/2051-5960-1-83
  • [Show abstract] [Hide abstract]
    ABSTRACT: The design of a structurally defined helical assembly is described that involves recoding of the amino acid sequence of peptide GCN4-pAA. In solution and the crystalline state, GCN4-pAA adopts a 7-helix bundle structure that resembles a supramolecular lock-washer. Structurally informed mutagenesis of the sequence of GCN4-pAA afforded peptide 7HSAP1, which undergoes self-association into a nanotube via non-covalent interactions between complementary interfaces of the coiled-coil lock washer structures. Biophysical measurements conducted in solution and the solid-state over multiple length-scales of structural hierarchy are consistent with the self-assembly of nanotube structures derived from the 7-helix bundle sub-units, in which the dimensions of the supramolecular assemblies are similar to those observed in the crystal structure of GCN4-pAA. Fluorescence studies of the interaction of 7HSAP1 with the solvatochromic fluorophore PRODAN indicated that the nanotubes could encapsulate shape-appropriate small-molecules with high binding affinity.
    Journal of the American Chemical Society 09/2013; 135(41). DOI:10.1021/ja4074529 · 12.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Elaborate morphology: The αSβ1 peptide, a fragment of α-synuclein, assembles into flat tapes consisting of a peptide bilayer, which can be modeled based on the cross-β structure found in amyloid proteins. The tapes are stabilized by hydrogen bonding, whilst the amphiphilic nature of the peptide results in the thin bilayer structure. To further stabilize the structure, these tapes may twist to form helical tapes, which subsequently close into nanotubes.
    Angewandte Chemie International Edition 02/2013; 52(8). DOI:10.1002/anie.201207699 · 11.26 Impact Factor

Publication Stats

8k Citations
708.59 Total Impact Points


  • 2015
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2005–2015
    • 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