A5002908788- Neuroscience and Neuropharmacology Research
- Alzheimer's disease research and treatments
- Cellular transport and secretion
- Receptor Mechanisms and Signaling
- Hippo pathway signaling and YAP/TAZ
- Memory and Neural Mechanisms
- Computational Drug Discovery Methods
- Molecular Sensors and Ion Detection
- Neuropeptides and Animal Physiology
- Wnt/β-catenin signaling in development and cancer
- Axon Guidance and Neuronal Signaling
- Biochemical Analysis and Sensing Techniques
- Biochemical effects in animals
- Pharmacological Effects and Assays
- Ion channel regulation and function
- Protein Kinase Regulation and GTPase Signaling
- Renin-Angiotensin System Studies
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Protein Structure and Dynamics
- Photoreceptor and optogenetics research
- Neurotransmitter Receptor Influence on Behavior
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Cancer-related gene regulation
- Neuroinflammation and Neurodegeneration Mechanisms
Centre National de la Recherche Scientifique
2009-2025
Université de Bordeaux
2016-2025
Wyss Center for Bio and Neuroengineering
2023
Institut Interdisciplinaire de Neuroscience
2016-2022
Icahn School of Medicine at Mount Sinai
2008-2013
Institut de Génomique Fonctionnelle
2007-2011
Université de Montpellier
2005-2011
Inserm
2005-2011
New York University
2011
The 5-hydroxytryptamine type 4 receptor (5-HT4R) is involved in learning, feeding, respiratory control and gastrointestinal transit. This one of the G-protein-coupled receptors for which alternative mRNA splicing generates most variants that differ their C-terminal extremities. Some 5-HT4R (a, e f) express canonical PDZ ligands at C-termini. Here, we have examined whether some mouse associate with specific sets proteins, using a proteomic approach based on peptide-affinity chromatography,...
Abstract In Alzheimer's disease (AD), the distribution of amyloid precursor protein (APP) and its fragments other than beta, has not been fully characterized. Here, we investigate APP in human AD brain samples mouse models reference to proteases, synaptic proteins, histopathological features characteristic brain, by combining an extensive set histological analytical tools. We report that prominent somatic observed control patients remarkably vanishes benefit dense accumulations extra‐somatic...
The discovery that class C G protein-coupled receptors (GPCRs) function as obligatory dimeric entities has generated major interest in GPCR oligomerization. Oligomerization now appears to be a common feature among all classes. However, the functional significance of this process remains unclear because, vitro, some monomeric GPCRs, such rhodopsin and β2-adrenergic receptors, activate proteins. By using wild type mutant serotonin 4 (5-HT4Rs) (including 5-HT4-RASSL) expressed COS-7 cells...
Abstract Mutations of the intramembrane protease presenilin (PS) or its main substrate, amyloid precursor protein (APP), cause early-onset form Alzheimer disease. PS and APP interact with proteins neurotransmitter release machinery without identified functional consequences. Here we report that genetic deletion markedly decreases presynaptic levels Ca 2+ sensor synaptotagmin-7 (Syt7) leading to impaired synaptic facilitation replenishment vesicles. The regulation Syt7 expression by occurs...
In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal via their axons, mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on proximal dendrites (PCs). MfB/TE have distinctive "detonator" properties due low initial release probability presynaptic facilitation. molecular mechanisms shaping morpho-functional are still poorly understood, though alterations in morphology associated Down syndrome,...
The 5-hydroxytryptamine 4 (5-HT ) receptors have recently emerged as key modulators of learning, memory, and cognitive processes. In neurons, Rs) activate cAMP production protein kinase A (PKA); however, nothing is known about their ability to another signaling pathway involved in learning memory: the extracellular signal-regulated (ERK) pathway. Here, we show that 5-HT R stimulation, primary produced a potent but transient activation ERK Surprisingly, this was mostly PKA independent....
The mouse 5-hydroxytryptamine<sub>4a</sub> (5-HT<sub>4a</sub>) receptor is an unusual member of the G protein-coupled superfamily because it possesses two separate carboxyl-terminal palmitoylation sites, which may allow to adopt different conformations in agonist-dependent manner (<i>J Biol Chem</i><b>277:</b>2534–2546, 2002). By targeted mutation proximal (Cys-328/329) or distal (Cys-386) a combination both, we generated 5-HT<sub>4a</sub> variants with distinct functional characteristics....
γ-Secretase inhibitors (GSIs) are drugs used in research to inhibit production of Aβ and clinical trials treat Alzheimer's disease (AD). They proteolytic activities γ-secretase noncompetitively by unknown mechanisms. Here, we cortical neuronal cultures expressing endogenous levels enzymes substrates study the effects GSIs on structure function γ-secretase. We show that stabilize interactions between C-terminal fragment presenilin (PS-CTF), central component complex, its partners...
Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the of perforant path, which provides main excitatory input hippocampus. To elucidate molecular mechanisms underlying these synapses, we performed explorative proteomic study dentate terminal zone path. The outer two-thirds layer gyrus, where path located, was microdissected from five subjects with...
The gamma-secretase complex cleaves many transmembrane proteins, including amyloid precursor protein, EphB and ErbB tyrosine kinase receptors, Notch1 adhesion factors. Presenilin 1, the catalytic subunit of gamma-secretase, associates with cadherin/catenin cell-cell adhesion/communication system promotes cadherin processing (Georgakopoulos, A., et al. (1999) Mol. Cell 4, 893-902; Marambaud, P., (2002) EMBO J. 21, 1948-1956), but mechanism by which cadherins associate is unclear. Here we...
Kainate receptors (KARs) form a family of ionotropic glutamate that regulate the activity neuronal networks by both presynaptic and postsynaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence epileptic symptoms Alzheimer's disease (AD) patients questions role KARs AD. Here we investigated whether synaptic expression function was impaired mouse models We addressed this question immunostaining electrophysiology at synapses between mossy...
Reverse signaling through the ephrinB ligands is important for several morphogenetic events, such as axon guidance, neuronal plasticity, spine maturation, and synaptogenesis. Signaling initiated by binding of EphB receptors to ligands, stimulating their tyrosine phosphorylation via an unclear mechanism. Here we show that this mechanism involves presenilin1 (PS1)/γ-secretase regulation phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk protein (PAG/Cbp), adaptor...
Synaptic degeneration has been reported as one of the best pathological correlates cognitive deficits in Alzheimer's disease. However, location these synaptic alterations within hippocampal sub-regions, vulnerability presynaptic versus postsynaptic compartments, and biological mechanisms for impairments remain unknown. Here, we performed immunofluorescence labelling different proteins fixed paraffin-embedded human sections report reduced levels several neurotransmitter release machinery...
The use of human post-mortem brain material is great value when investigating which pathological mechanisms occur in brain, and to avoid translational problems have for example been evident translating animal research into Alzheimer disease (AD) clinical trials. amyloid β (Aβ)-peptide, its precursor protein (APP) the intermediate APP-c-terminal fragments (APP-CTFs) are all important players AD pathogenesis. In order elucidate APP CTF that most common tissue different species developmental...
The organization of spatial information, including pattern completion and separation processes, relies on the hippocampal circuits, yet molecular cellular mechanisms underlying these two processes are elusive. Here, we find that loss Vangl2, a core PCP gene, results in opposite effects processes. Mechanistically, show Vangl2 maintains young postmitotic granule cells an immature state, providing increased input for separation. genetic ablation disrupts cell morpho-functional maturation...
Photobiomodulation (PBM), the process of exposing tissue to red or near-infrared light, has become a topic great interest as therapy for diverse pathologies, including neurodegenerative disorders. Here, we aimed evaluate potential beneficial effect PBM on Alzheimer's disease (AD) using behavioral and histological readouts from well-established transgenic murine AD model (5xFAD mice) in randomized fully blinded long-term in-vivo study following GLP (Good Laboratory Practices) guidelines. The...
Abnormally high concentrations of extracellular glutamate in the brain may cause neuronal damage via excitotoxicity. Thus, tight regulation release is critical to function and survival. Excitotoxicity caused mainly by overactivation extrasynaptic NMDA receptor (NMDAR) results specific cellular changes, including calcium-induced activation calpain proteases. Here, we report that presenilin-1 (PS1) null mouse cortical cultures have increased amounts calpain-dependent spectrin breakdown...
The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential study and understanding roles in health disease. Herein, we report on pharmacological characterization (S)-2-hydroxyhistidine (2a) (S)-2-mercaptohistidine (2b) mediators glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all transporters investigated, 2b selectivity homomeric GluK3 with affinities low...
Summary In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal via their axons, mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on proximal dendrites (PCs). MfB/TE have distinctive “detonator” properties due low intitial release probability presynaptic facilitation. molecular mechanisms shaping morpho-functional are still poorly understood, though alterations in morphology associated Down...