1. COB231 targets amyloid plaques in post-mortem human brain tissue and in an Alzheimer mouse model
- Author
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Martine Demeunynck, Catherine Ghezzi, M. Sallanon, Frank M. LaFerla, Dominique Garin, Danièle Marti-Battle, David Meyronet, Angélique Virgone-Carlotta, Michel Dubois-Dauphin, Pascale Perret, Philippe Millet, Bülent Gözel, Monique Touret, Sabine Chierici, Nathalie Streichenberger, Fatima Oukhatar, Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires (DCM - I2BM), Département de Chimie Moléculaire (DCM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires de Genève (HUG), University of Geneva [Switzerland], Hospices Civils de Lyon (HCL), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Radiopharmaceutiques biocliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Radiopharmaceutiques Biocliniques, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Perret, Pascale, and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)
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Pathology ,Hippocampus ,Plaque, Amyloid ,MESH: Microscopy, Fluorescence ,Biochemistry ,Mice ,ddc:616.89 ,Image Processing, Computer-Assisted ,MESH: Animals ,Cellular localization ,MESH: Proflavine ,Brain ,Human brain ,MESH: Fluorescent Dyes ,Immunohistochemistry ,MESH: Image Processing, Computer-Assisted ,MESH: Plaque, Amyloid ,MESH: Staining and Labeling ,medicine.anatomical_structure ,Female ,Autopsy ,Proflavine ,Genetically modified mouse ,medicine.medical_specialty ,Aminoacridine ,Amyloid ,MESH: Mice, Transgenic ,Mice, Transgenic ,[SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,Biology ,Sensitivity and Specificity ,[SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,Cellular and Molecular Neuroscience ,MESH: Brain ,In vivo ,Alzheimer Disease ,MESH: Mice, Inbred C57BL ,medicine ,Animals ,Humans ,Viability assay ,MESH: Mice ,Fluorescent Dyes ,MESH: Humans ,Staining and Labeling ,MESH: Immunohistochemistry ,MESH: Aminacrine ,MESH: Sensitivity and Specificity ,Mice, Inbred C57BL ,Aminacrine ,Disease Models, Animal ,Microscopy, Fluorescence ,MESH: Autopsy ,MESH: Disease Models, Animal ,MESH: Female ,MESH: Alzheimer Disease - Abstract
International audience; Previous works have shown the interest of naturally fluorescent proflavine derivatives to label Abeta deposits in vitro. This study aimed to further characterize the properties of the proflavine 3-acetylamino-6-[3-(propargylamino)propanoyl]aminoacridine (COB231) derivative as a probe. This compound was therefore evaluated on human post-mortem and mice brain slices and in vivo in 18-month-old triple transgenic mice APPswe, PS1M146V and tauP301L (3xTgAD) mice presenting the main characteristics of Alzheimer's disease (AD). COB231 labelled amyloid plaques on brain slices of AD patients, and 3xTgAD mice at 10 and 0.1 μM respectively. However, no labelling of the neurofibrillary tangle-rich areas was observed either at high concentration or in the brain of fronto-temporal dementia patients. The specificity of this mapping was attested in mice using Thioflavin S and IMPY as positive controls of amyloid deposits. After intravenous injection of COB231 in old 3xTgAD mice, fluorescent amyloid plaques were detected in the cortex and hippocampus, demonstrating COB231 blood–brain barrier permeability. We also controlled the cellular localization of COB231 on primary neuronal cultures and showed that COB231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB231 (< 10%) for the highest concentration (100 μM).
- Published
- 2015
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