ORCID Profile
0000-0002-6261-4230
Current Organisations
University of Lille
,
INSERM
,
CNRS
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Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.NEUROBIOLAGING.2014.05.005
Abstract: Tau has been implicated in the organization, stabilization, and dynamics of microtubules. In Alzheimer's disease and more than 20 neurologic disorders tau missorting, hyperphosphorylation, and aggregation is a hallmark. They are collectively referred to as tauopathies. Although the impact of human tauopathies on cognitive processes has been explored in transgenic mouse models, the functional consequences of tau deletion on cognition are far less investigated. Here, we subjected tau knock-out (KO) mice to a battery of neurocognitive, behavioral, and electrophysiological tests. Although KO and wild-type mice were indistinguishable in motor abilities, exploratory and anxiety behavior, KO mice showed impaired contextual and cued fear conditioning. In contrast, extensive spatial learning in the water maze resulted in better performance of KO mice during acquisition. In electrophysiological experiments, basal synaptic transmission and paired-pulse facilitation in the hippoc al CA1-region were unchanged. Interestingly, deletion of tau resulted in severe deficits in long-term potentiation but not long-term depression. Our results suggest a role of tau in certain cognitive functions and implicate long-term potentiation as the relevant physiological substrate.
Publisher: American Chemical Society (ACS)
Date: 06-10-2021
DOI: 10.1021/ACSCHEMNEURO.1C00488
Abstract: Deformation, compression, or stretching of brain tissues cause diffuse axonal injury (DAI) and induce structural and functional alterations of astrocytes, the most abundant cell type in the brain. To gain further insight into the role of mechanically activated astrocytes on neuronal networks, this study was designed to investigate whether cytokines released by mechanically activated astrocytes can affect the growth and synaptic connections of cortical neuronal networks. Astrocytes were cultivated on elastic membranes and subjected to repetitive mechanical insults, whereas well-defined protein micropatterns were used to form standardized neuronal networks. GFAP staining showed that astrocytes were mechanically activated after two cycles of stretch and mesoscale discovery assays indicated that injured astrocytes released four major cytokines. To understand the role of these cytokines, neuronal networks were cultured with the supernatant of healthy or mechanically activated astrocytes, and the in idual contribution of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) was studied. We found that the supernatant of two-cycle stretched astrocytes decreased presynaptic terminals and indicated that TNF-α must be considered a key player of the synaptic loss. Furthermore, our results indicate that cytokines released by injured astrocytes significantly modulate the balance between TNFR1 and TNFR2 receptors by enhancing R2 receptors. We demonstrated that TNF-α is not involved in this process, suggesting a predominant role of other secreted cytokines. Together, these results contribute to a better understanding of the consequences of repetitive astrocyte deformations and highlight the role of inflammatory signaling pathways in synaptic plasticity and modulation of TNFR1 and TNFR2 receptors.
Publisher: Portland Press Ltd.
Date: 26-07-2010
DOI: 10.1042/BST0380967
Abstract: Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.NLM.2010.12.005
Abstract: We evaluated various forms of hippoc us-dependent learning and memory, and hippoc al synaptic plasticity in THY-Tau22 transgenic mice, a murine tauopathy model that expresses double-mutated 4-repeat human tau, and shows neuropathological tau hyperphosphorylation and aggregation throughout the brain. Focussing on hippoc us, immunohistochemical studies in aged THY-Tau22 mice revealed prominent hyper- and abnormal phosphorylation of tau in CA1 region, and an increase in glial fibrillary acidic protein (GFAP) in hippoc us, but without signs of neuronal loss. These mice displayed spatial, social, and contextual learning and memory defects that could not be reduced to subtle neuromotor disability. The behavioral defects coincided with changes in hippoc al synaptic functioning and plasticity as measured in paired-pulse and novel long-term depression protocols. These results indicate that hippoc al tauopathy without neuronal cell loss can impair neural and behavioral plasticity, and further show that transgenic mice, such as the THY-Tau22 strain, might be useful for preclinical research on tauopathy pathogenesis and possible treatment.
Publisher: Public Library of Science (PLoS)
Date: 15-04-2011
Publisher: Springer Science and Business Media LLC
Date: 10-02-2009
DOI: 10.1038/MP.2009.10
Publisher: Frontiers Media SA
Date: 08-10-2020
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.BBR.2012.12.008
Abstract: THY-Tau22 mice constitute an animal model for tau aggregation, a hallmark in Alzheimer's disease (AD) and Tauopathies. Our previous studies have shown learning and memory deficits and changes in synaptic plasticity in the hippoc us in THY-Tau22 mice that are consistent with the learning impairments seen in AD-patients. However, behavioral disturbances are the most important problems in the management of AD and are major determinants of nursing home placement. Thus, we hypothesized that THY-Tau22 mice would demonstrate, in addition to the cognitive impairments, at least some behavioral and psychological signs and symptoms of dementia (BPSD). We found that 12 months old THY-Tau22 mice, relative to wild-type (WT) littermates display increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. Moreover, these changes were linked to a decreased hippoc al concentration in serotonin, or 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin. Together these data corroborate the usefulness of the model in preclinical evaluations of therapeutic strategies that aim to reverse cognitive defects and alleviate BPSD in the human disease.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2015
Publisher: Springer Science and Business Media LLC
Date: 02-12-2014
DOI: 10.1038/MP.2014.151
Abstract: Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippoc al plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippoc al long-term depression. These effects were concomitant with a normalization of the hippoc al glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.
Publisher: Oxford University Press (OUP)
Date: 10-11-2014
DOI: 10.1093/BIOINFORMATICS/BTU741
Abstract: Motivation: Extracellular vesicles (EVs) are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for EV-related publications and vesicular components are currently challenging. Results: We present an improved version of EVpedia, a public database for EVs research. This community web portal contains a database of publications and vesicular components, identification of orthologous vesicular components, bioinformatic tools and a personalized function. EVpedia includes 6879 publications, 172 080 vesicular components from 263 high-throughput datasets, and has been accessed more than 65 000 times from more than 750 cities. In addition, about 350 members from 73 international research groups have participated in developing EVpedia. This free web-based database might serve as a useful resource to stimulate the emerging field of EV research. Availability and implementation: The web site was implemented in PHP, Java, MySQL and Apache, and is freely available at evpedia.info. Contact: ysgho@postech.ac.kr
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.BBAGRM.2018.06.006
Abstract: Tauopathies, such as Alzheimer's disease, are characterized by intracellular aggregates of insoluble Tau proteins. Originally described as a microtubule binding protein, recent studies demonstrated additional physiological roles for Tau. The fact that a single protein can regulate multiple cellular functions has posed challenge in terms of understanding mechanistic cues behind the pathology. Here, we used tandem-affinity purification methodology coupled to mass spectrometry to identify novel interaction partners. We found that Tau interacts with DDX6, a DEAD box RNA helicase involved in translation repression and mRNA decay as well as in the miRNA pathway. Our results demonstrate that Tau increases the silencing activity of the miRNA let-7a, miR-21 and miR-124 through DDX6. Importantly, Tau mutations (P301S, P301L) found in the inherited tauopathies, frontotemporal dementia and parkinsonism linked to chromosome 17, disrupt Tau/DDX6 interaction and impair gene silencing by let-7a. Altogether, these data demonstrated a new unexpected role for Tau in regulating miRNA activity.
No related grants have been discovered for Luc BUEE.