David T. Hickman
École Polytechnique Fédérale de Lausanne
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Featured researches published by David T. Hickman.
Proceedings of the National Academy of Sciences of the United States of America | 2007
Andreas Muhs; David T. Hickman; Maria Pihlgren; Nathalie Chuard; Valérie Giriens; Carine Meerschman; Ingrid Van der Auwera; Fred Van Leuven; Masae Sugawara; Marie-Catherine Weingertner; Burkhard Bechinger; Ruth Greferath; Nadine Kolonko; Luitgard Nagel-Steger; Detlev Riesner; Roscoe O. Brady; Andrea Pfeifer; Claude Nicolau
We investigated the therapeutic effects of two different versions of Aβ1–15 (16) liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetra-palmitoylated amyloid 1–15 peptide (palmAβ1–15), or with amyloid 1–16 peptide (PEG-Aβ1–16) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmAβ1–15 liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-Aβ1–16 had no such effect. Immunoglobulins that were generated were predominantly of the IgG class with palmAβ1–15, whereas those elicited by PEG-Aβ1–16 were primarily of the IgM class. The IgG subclasses of the antibodies generated by both vaccines were mostly IgG2b indicating noninflammatory Th2 isotype. CD and NMR revealed predominantly β-sheet conformation of palmAβ1–15 and random coil of PEG-Aβ1–16. We conclude that the association with liposomes induced a variation of the immunogenic structures and thereby different immunogenicities. This finding supports the hypothesis that Alzheimers disease is a “conformational” disease, implying that antibodies against amyloid sequences in the β-sheet conformation are preferred as potential therapeutic agents.
PLOS ONE | 2013
Clara Theunis; Natalia Crespo-Biel; Valerie Gafner; Maria Pihlgren; María Pilar López-Deber; Pedro Reis; David T. Hickman; Oskar Adolfsson; Nathalie Chuard; Dorin Mlaki Ndao; Peter Borghgraef; Herman Devijver; Fred Van Leuven; Andrea Pfeifer; Andreas Muhs
Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimers disease. The unmet need of effective therapy for Alzheimers disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuro-inflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimers disease.
Journal of Biological Chemistry | 2011
David T. Hickman; María Pilar López-Deber; Dorin Mlaki Ndao; Alberto B. Silva; Deepak Nand; Maria Pihlgren; Valérie Giriens; Rime Madani; Annie St-Pierre; Hristina Karastaneva; Luitgard Nagel-Steger; Dieter Willbold; Detlev Riesner; Claude Nicolau; Marc Baldus; Andrea Pfeifer; Andreas Muhs
Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be modulated post-liposome assembly by the addition of distinct small molecule β-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing β-sheet aggregated lipopeptide (Palm1–15) induced polyclonal IgG antibodies that specifically recognized β-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases, such as Alzheimer disease.
Angewandte Chemie | 2013
Eline J. Koers; María Pilar López-Deber; Markus Weingarth; Deepak Nand; David T. Hickman; Dorin Mlaki Ndao; Pedro Reis; Anne Granet; Andrea Pfeifer; Andreas Muhs; Marc Baldus
Keywords: Alzheimers disease ; dynamic nuclear polarization ; liposomal vaccines ; NMR spectroscopy ; -amyloid peptide Reference EPFL-ARTICLE-190124doi:10.1002/anie.201303374View record in Web of Science Record created on 2013-11-04, modified on 2017-05-12
Blood | 2013
Maria Pihlgren; Alberto B. Silva; Rime Madani; Valérie Giriens; Ying Waeckerle-Men; Antonia Fettelschoss; David T. Hickman; María Pilar López-Deber; Dorin Mlaki Ndao; Marija Vukicevic; Anna Lucia Buccarello; Valerie Gafner; Nathalie Chuard; Pedro Reis; Kasia Piorkowska; Andrea Pfeifer; Thomas M. Kündig; Andreas Muhs; Pål Johansen
Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell-independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-β (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.
PLOS ONE | 2016
Pavel V. Belichenko; Rime Madani; Lorianne Rey-Bellet; Maria Pihlgren; Ann Becker; Adeline Plassard; Stephanie Vuillermot; Valérie Giriens; Rachel L. Nosheny; Alexander M. Kleschevnikov; Janice S. Valletta; Sara K. S. Bengtsson; Gordon R. Linke; Michael T. Maloney; David T. Hickman; Pedro Reis; Anne Granet; Dorin Mlaki; María Pilar López-Deber; Long Do; Nishant Singhal; Eliezer Masliah; Matthew L. Pearn; Andrea Pfeifer; Andreas Muhs; William C. Mobley
In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS.
Bioorganic & Medicinal Chemistry Letters | 2017
Nampally Sreenivasachary; Heiko Kroth; Pascal Benderitter; Anne Hamel; Yvan Varisco; David T. Hickman; Wolfgang Froestl; Andrea Pfeifer; Andreas Muhs
The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.
PLOS ONE | 2014
Maria Pilar Lopez Deber; David T. Hickman; Deepak Nand; Marc Baldus; Andrea Pfeifer; Andreas Muhs
Aggregation of amyloid beta (Aβ) into oligomers and fibrils is believed to play an important role in the development of Alzheimer’s disease (AD). To gain further insight into the principles of aggregation, we have investigated the induction of β-sheet secondary conformation from disordered native peptide sequences through lipidation, in 1–2% hexafluoroisopropanol (HFIP) in phosphate buffered saline (PBS). Several parameters, such as type and number of lipid chains, peptide sequence, peptide length and net charge, were explored keeping the ratio peptide/HFIP constant. The resulting lipoconjugates were characterized by several physico-chemical techniques: Circular Dichroism (CD), Attenuated Total Reflection InfraRed (ATR-IR), Thioflavin T (ThT) fluorescence, Dynamic Light Scattering (DLS), solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy and Electron Microscopy (EM). Our data demonstrate the generation of β-sheet aggregates from numerous unstructured peptides under physiological pH, independent of the amino acid sequence. The amphiphilicity pattern and hydrophobicity of the scaffold were found to be key factors for their assembly into amyloid-like structures.
Journal of Alzheimer's Disease | 2017
Clara Theunis; Oskar Adolfsson; Natalia Crespo-Biel; Kasia Piorkowska; Maria Pihlgren; David T. Hickman; Valerie Gafner; Peter Borghgraef; Herman Devijver; Andrea Pfeifer; Fred Van Leuven; Andreas Muhs
The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer’s disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer’s disease.
Alzheimers & Dementia | 2017
Andre Mueller; Heiko Kroth; Hanno Schieferstein; Mathias Berndt; Felix Oden; Francesca Capotosti; Jérôme Molette; Tanja Juergens; Vincent Darmency; Heribert Schmitt-Willich; David T. Hickman; Gilles Tamagnan; Andrea Pfeifer; Ludger Dinkelborg; Andreas Muhs; Andrew Stephens
from 65 to 85% (FTD vs EAOD: 82%, EOAD vs Depression: 83%, FTD vs Depression: 82%). Conclusions: Novel computational tools can be useful in clinical practice and provide comprehensive information supporting clinicians in decisionmaking processes. ASS analyzed in a univariate way was moderately adequate, with poor accuracy compared with its implementation in an SVM classifier. SVM using whole brain segmentation yielded the highest diagnostic accuracies. Furthermore, SVM performed as well as published accuracies of pathophysiological markers of AD to distinguish this etiology from other dementias and depression. Implementation of whole brain SVM classification in clinical routine could represent a valuable diagnostic tool.