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COB231 targets amyloid plaques in post‐mortem human brain tissue and in an Alzheimer mouse model
Author(s) -
Garin Dominique,
VirgoneCarlotta Angélique,
Gözel Bülent,
Oukhatar Fatima,
Perret Pascale,
MartiBattle Danièle,
Touret Monique,
Millet Philippe,
DuboisDauphin Michel,
Meyronet David,
Streichenberger Nathalie,
Laferla Frank M.,
Demeunynck Martine,
Chierici Sabine,
Salla Marcelle Moulin,
Ghezzi Catherine
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12951
Subject(s) - in vivo , pathology , genetically modified mouse , chemistry , amyloid (mycology) , hippocampal formation , fluorescence , hippocampus , alzheimer's disease , thioflavin , biochemistry , microbiology and biotechnology , neuroscience , transgene , biology , medicine , disease , physics , quantum mechanics , gene
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 ( COB 231) 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 (3xTg AD ) mice presenting the main characteristics of Alzheimer's disease ( AD ). COB 231 labelled amyloid plaques on brain slices of AD patients, and 3xTg AD 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 COB 231 in old 3xTg AD mice, fluorescent amyloid plaques were detected in the cortex and hippocampus, demonstrating COB 231 blood–brain barrier permeability. We also controlled the cellular localization of COB 231 on primary neuronal cultures and showed that COB 231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB 231 (< 10%) for the highest concentration (100 μM).Previous work has shown that naturally fluorescent proflavine derivatives label Abeta plaques. Our aim was to further characterize the properties of one of them: 3‐acetylamino‐6‐[3‐(propargylamino) propanoyl]aminoacridine (COB231). We demonstrated the Abeta deposit binding properties of COB231 in vitro on Alzheimer (AD) patient brain slices (see image showing COB231 labelling of Abeta deposits), and in vivo in an AD mice model. These results are particularly attractive with regard to the flexible chemistry of COB231 that allows further radiolabelling for in vivo imaging or combination with a therapeutic agent targeting Abeta aggregates.