| Title: |
Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models |
| Authors: |
Canet, Geoffrey; Zussy, Charleine; Vitalis, Mathieu; Morin, Françoise; Chevallier, Nathalie; Hunt, Hazel; Claeysen, Sylvie; Blaquière, Marine; Marchi, Nicola; Planel, Emmanuel; Meijer, Onno; Desrumaux, Catherine; Givalois, Laurent |
| Contributors: |
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); Faculté de médecine de l'Université Laval Québec (ULaval); Université Laval Québec (ULaval); Centre de recherche du CHU de Québec-Université Laval (CRCHUQ); CHU de Québec–Université Laval; Université Laval Québec (ULaval)-Université Laval Québec (ULaval); Corcept Therapeutics; Institut de Génomique Fonctionnelle (IGF); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN); Leiden University Medical Center Leiden (LUMC); Universiteit Leiden = Leiden University-Universiteit Leiden = Leiden University; Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc Dijon (UNICANCER/CRLCC-CGFL); UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Établissement Français du Sang Bourgogne-Franche-Comté Besançon (EFS BFC - Besançon); Établissement Français du Sang La Plaine Saint-Denis (EFS)-Établissement Français du Sang La Plaine Saint-Denis (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Marie et Louis Pasteur (UMLP); Université Bourgogne Franche-Comté COMUE (UBFC)-Université Bourgogne Franche-Comté COMUE (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon; Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM)-Université Bourgogne Europe (UBE); Centre National de la Recherche Scientifique (CNRS); Study supported by INSERM, CNRS, University of Montpellier and EPHE annual resources (France), by a grant from ‘France Alzheimer’ and ‘Fédération pour la Recherche sur le Cerveau’ (Grant AAP SM2016#1512 - LG) and by a grant from the ‘Agence Nationale de la Recherche’ (ANR) under the programme ‘Investissements d'Avenir’ (ANR-11-LABEX-0021-LipSTIC - CD).LG, NM, CZ and MV were supported by grants from the ‘Agence Nationale de la Recherche’ (no. ANR-AAP2022-R22102FF-EpiNeurAge); the ‘Fondation pour la Recherche Médicale’ (no. MND202003011477-OPA); and the ‘University of Montpellier Program of Excellence’ (no. MUSE-AAP20REC-FRS09-GAiA).GC is supported by a PhD Grant from the University of Montpellier, France (CBS2 PhD programme), and by a postdoctoral fellowship from the Alzheimer Society of Canada.; ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011) |
| Source: |
ISSN: 0007-1188. |
| Publisher Information: |
CCSD; Wiley |
| Publication Year: |
2025 |
| Collection: |
Inserm: HAL (Institut national de la santé et de la recherche médicale) |
| Subject Terms: |
HPA axis; neuroinflammation; glucocorticoid receptors; Tau protein; J20 mice; Amyloid‐β peptide; Alzheimer's disease; 5xFAD mice; [SCCO.NEUR]Cognitive science/Neuroscience; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology |
| Description: |
International audience ; Background and Purpose: Exposure to chronic stress and high levels of glucocorticoid hormones in adulthood has been associated with cognitive deficits and increased risk of Alzheimer's disease (AD). Dazucorilant has recently emerged as a selective glucocorticoid receptor (NR3C1) modulator, exhibiting efficacy in counteracting amyloid‐ β toxicity in an acute model of AD. We aim to assess the therapeutic potential of dazucorilant in reversing amyloid and tau pathologies through the inhibition of glucocorticoid receptor pathological activity, and providing additional evidence for its consideration in AD treatment.Experimental Approach: The efficacy of dazucorilant was evaluated in two transgenic mouse models of amyloid pathology. The slowly progressing J20 and the aggressively pathological 5xFAD mice. Behavioural analysis was conducted to evaluate welfare, cognitive performances and anxiety levels. The activity of the glucocorticoid receptor system, neuroinflammation, amyloid burden and tau phosphorylation were examined in hippocampi. Key Results: In both AD models, chronic treatment with dazucorilant improved working and long‐term spatial memories along with the inhibition of glucocorticoid receptor‐dependent pathogenic processes and the normalization of plasma glucocorticoid levels. Dazucorilant treatment also resulted in a reduction in tau hyperphosphorylation and amyloid production and aggregation. Additionally, dazucorilant seemed to mediate a specific re‐localization of activated glial cells onto amyloid plaques in J20 mice, suggesting a restoration of physiological neuroinflammatory processes.Conclusion and Implications Dazucorilant exhibited sustained disease‐modifying effects in two AD models. Given that this compound has demonstrated safety and tolerability in human subjects, our results provide pre‐clinical support for conducting clinical trials to evaluate its potential in AD. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39891319; PUBMED: 39891319 |
| DOI: |
10.1111/bph.17457 |
| Availability: |
https://hal.science/hal-04928530; https://hal.science/hal-04928530v1/document; https://hal.science/hal-04928530v1/file/Canet%20et%20al%202025.pdf; https://doi.org/10.1111/bph.17457 |
| Rights: |
https://hal.science/licences/copyright/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.CE7CA99B |
| Database: |
BASE |