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5 results on '"Geoffrey Canet"'

1. Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets

Author

Geoffrey Canet, Célia Hernandez, Charleine Zussy, Nathalie Chevallier, Catherine Desrumaux, Laurent Givalois, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Givalois, Laurent, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Aging, Cognitive Neuroscience, Mini Review, CRH (corticotropin-releasing hormone), 11β hydroxysteroid dehydrogenase, AVP (arginine vasopressin), lcsh:RC321-571, stress-related disorder, HPA axis (hypothalamus-pituitary-adrenal), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], glucococorticoids, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Alzheimer’s disease, ComputingMilieux_MISCELLANEOUS, Neuroscience
Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (senile plaques and neurofibrillary tangles), effective treatments are still lacking. Sporadic AD forms (98% of all cases) are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures (prefrontal cortex and hippocampus) and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.

Published
2019
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2. New selective glucocorticoid receptor modulators reverse amyloid-β peptide–induced hippocampus toxicity

Author

Hazel Hunt, Joseph K. Belanoff, Nathalie Chevallier, Catherine Desrumaux, Fanny Pineau, Geoffrey Canet, Laurent Givalois, Matthias Ollivier, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Male, 0301 basic medicine, Aging, Pituitary-Adrenal System, Hippocampus, Hippocampal formation, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Glucocorticoid receptor, Molecular Targeted Therapy, ComputingMilieux_MISCELLANEOUS, General Neuroscience, Antiglucocorticoid, Mifepristone, 3. Good health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, medicine.symptom, medicine.drug, Hypothalamo-Hypophyseal System, medicine.medical_specialty, Biology, Heterocyclic Compounds, 4 or More Rings, 03 medical and health sciences, Receptors, Glucocorticoid, Alzheimer Disease, Internal medicine, medicine, Animals, Cognitive Dysfunction, Glucocorticoids, Neuroinflammation, Cognitive deficit, Aza Compounds, Amyloid beta-Peptides, Dose-Response Relationship, Drug, Isoquinolines, medicine.disease, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Pyrazoles, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology
Abstract

In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-β peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment.

Published
2016
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3. The GR-ANXA1 pathway is a pathological player and a candidate target in epilepsy

Author

Etienne Audinat, Marine Blaquiere, Madeeha H Sheikh, Chris P. M. Reutelingsperger, Laura Rossini, Egle Solito, Geoffrey Canet, Wendy Klement, Laurent Givalois, Chiara Pastori, Rita Garbelli, Emma Zub, Nicola Marchi, Frédéric de Bock, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), DiSAA, Università degli studi di Milano [Milano], Department of Psychatry and Behavioral Sciences and Center for Therapeutic Innovation, Department of Biochemistry, Maastricht University [Maastricht], Solito, Egle, RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, Biochemie, RS: CARIM - R1.02 - Vascular aspects thrombosis and haemostasis, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and Università degli Studi di Milano [Milano] (UNIMI)

Subjects
0301 basic medicine, Endogeny, Hippocampus, Biochemistry, Epileptogenesis, brain/peripheral inflammation, Mice, Epilepsy, 0302 clinical medicine, Glucocorticoid receptor, glucocorticoid receptor, Medicine, skin and connective tissue diseases, endogenous antiinflammatory signals, ComputingMilieux_MISCELLANEOUS, Kainic Acid, Brain, 3. Good health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Biotechnology, endogenous anti-inflammatory signal, Inflammation, 03 medical and health sciences, Receptors, Glucocorticoid, Immune system, INFLAMMATION, parasitic diseases, Genetics, Animals, Humans, Molecular Biology, Pathological, IL-6, business.industry, AnnexinA1, medicine.disease, annexin A1, Blood Cell Count, Mice, Inbred C57BL, 030104 developmental biology, Gene Expression Regulation, RESOLUTION, Immunology, epilepsy, sense organs, Corticosterone, business, 030217 neurology & neurosurgery, Annexin A1
Abstract

Immune changes occur in experimental and clinical epilepsy. Here, we tested the hypothesis that during epileptogenesis and spontaneous recurrent seizures (SRS) an impairment of the endogenous anti-inflammatory pathway glucocorticoid receptor (GR)-annexin A1 (ANXA1) occurs. By administrating exogenous ANXA1, we studied whether pharmacological potentiation of the anti-inflammatory response modifies seizure activity and pathophysiology. We used an in vivo model of temporal lobe epilepsy based on intrahippocampal kainic acid (KA) injection. Video-electroencephalography, molecular biology analyses on brain and peripheral blood samples, and pharmacological investigations were performed in this model. Human epileptic cortices presenting type II focal cortical dysplasia (IIa and b), hippocampi with or without hippocampal sclerosis (HS), and available controls were used to study ANXA1 expression. A decrease of phosphorylated (phospho-) GR and phospho-GR/tot-GR protein expression occurred in the hippocampus during epileptogenesis. Downstream to GR, the anti-inflammatory protein ANXA1 remained at baseline levels while inflammation installed and endured. In peripheral blood, ANXA1 and corticosterone levels showed no significant modifications during disease progression except for an early and transient increase poststatus epilepticus. These results indicate inadequate ANXA1 engagement over time and in these experimental conditions. By analyzing human brain specimens, we found that where significant inflammation exists, the pattern of ANXA1 immunoreactivity was abnormal because the typical perivascular ANXA1 immunoreactivity was reduced. We next asked whether potentiation of the endogenous anti-inflammatory mechanism by ANXA1 administration modifies the disease pathophysiology. Although with varying efficacy, administration of exogenous ANXA1 somewhat reduced the time spent in seizure activity as compared to saline. These results indicate that the anti-inflammatory GR-ANXA1 pathway is defective during experimental seizure progression. The prospect of pharmacologically restoring or potentiating this endogenous anti-inflammatory mechanism as an add-on therapeutic strategy for specific forms of epilepsy is proposed.

Published
2019
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4. Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

Author

Fanny Pineau, Charleine Zussy, Célia Hernandez, Hazel Hunt, Geoffrey Canet, Joseph K. Belanoff, Véronique Perrier, Joan Torrent, Nathalie Chevallier, Onno C. Meijer, Catherine Desrumaux, Laurent Givalois, Givalois, Laurent, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Corcept Therapeutics, Einthoven Laboratory, Department of Medicine, Division of Endocrinology, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Male, 0301 basic medicine, GSK-3 beta, Pituitary-Adrenal System, Biochemistry, Rats, Sprague-Dawley, Amyloid beta-Protein Precursor, 0302 clinical medicine, Glucocorticoid receptor, Adrenal Cortex Hormones, Amyloid precursor protein, Homeostasis, Phosphorylation, Prefrontal cortex, ComputingMilieux_MISCELLANEOUS, Behavior, Animal, biology, Chemistry, Pathophysiology, PDK1, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, Signal Transduction, Biotechnology, Hypothalamo-Hypophyseal System, medicine.medical_specialty, Cdk5, tau Proteins, 03 medical and health sciences, Receptors, Glucocorticoid, Alzheimer Disease, Internal medicine, ROCK, Genetics, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glucocorticoids, Molecular Biology, Amyloid beta-Peptides, Cyclin-dependent kinase 5, selective GR modulator, Rats, Disease Models, Animal, 030104 developmental biology, Endocrinology, Apoptosis, biology.protein, 030217 neurology & neurosurgery
Abstract

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-beta oligomers (oA beta), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation. We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oA beta impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oA beta potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of the HPA axis and a feed-forward effect on PFC GR sensitivity could participate in the etiology of AD, in perturbing A beta and Tau homeostasis. These results also reinforce the therapeutic potential of sGRm in AD.

Published
2019
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5. HIV Neuroinfection and Alzheimer’s Disease: Similarities and Potential Links?

Author

Geoffrey Canet, Chloé Dias, Audrey Gabelle, Yannick Simonin, Fabien Gosselet, Nicola Marchi, Alain Makinson, Edouard Tuaillon, Philippe Van de Perre, Laurent Givalois, Sara Salinas, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département des Maladies Infectieuses [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier]-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Boutin, Marion, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), École Pratique des Hautes Études (EPHE), and Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI)

Subjects
0301 basic medicine, Amyloid, [SDV]Life Sciences [q-bio], Inflammation, Disease, Blood–brain barrier, lcsh:RC321-571, neuroinflammation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, HIV-associated neurocognitive disorders, medicine, Dementia, hypothalamo-pituitary-adrenal axis, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neuroinflammation, ComputingMilieux_MISCELLANEOUS, business.industry, Neurodegeneration, viral neuroinfection, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, medicine.symptom, business, Neuroscience, Neurocognitive, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract

International audience; Environmental factors such as chemicals, stress and pathogens are now widely believed to play important roles in the onset of some brain diseases, as they are associated with neuronal impairment and acute or chronic inflammation. Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction and neurodegeneration that ultimately lead to dementia. Neuroinflammation also plays a prominent role in AD and possible links to viruses have been proposed. In particular, the human immunodeficiency virus (HIV) can pass the blood-brain barrier and cause neuronal dysfunction leading to cognitive dysfunctions called HIV-associated neurocognitive disorders (HAND). Similarities between HAND and HIV exist as numerous factors involved in AD such as members of the amyloid and Tau pathways, as well as stress-related pathways or blood brain barrier (BBB) regulators, seem to be modulated by HIV brain infection, leading to the accumulation of amyloid plaques or neurofibrillary tangles (NFT) in some patients. Here, we summarize findings regarding how HIV and some of its proteins such as Tat and gp120 modulate signaling and cellular pathways also impaired in AD, suggesting similarities and convergences of these two pathologies.

Published
2018
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