Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 May;182(9):1930-1956.
doi: 10.1111/bph.17457. Epub 2025 Jan 31.

Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models

Geoffrey Canet  1   2 , Charleine Zussy  1 , Mathieu Vitalis  1 , Françoise Morin  2 , Nathalie Chevallier  1 , Hazel Hunt  3 , Sylvie Claeysen  4 , Marine Blaquière  4 , Nicola Marchi  4 , Emmanuel Planel  2 , Onno C Meijer  5 , Catherine Desrumaux  1   6 , Laurent Givalois  1   2   7
Affiliations
Free article

Advancing Alzheimer's disease pharmacotherapy: efficacy of glucocorticoid modulation with dazucorilant (CORT113176) in preclinical mouse models

Geoffrey Canet et al. Br J Pharmacol. 2025 May.
Free article

Abstract

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.

Keywords: 5xFAD mice; Alzheimer's disease; Amyloid‐β peptide; HPA axis; J20 mice; Tau protein; glucocorticoid receptors; neuroinflammation.

PubMed Disclaimer

References

REFERENCES

    1. Alexander, S. P. H., Cidlowski, J. A., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Coons, L., Fuller, P. J., Korach, K. S., & Young, M. J. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Nuclear hormone receptors. British Journal of Pharmacology, 180, S223–S240. https://doi.org/10.1111/bph.16179
    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Ostrom, R., Papapetropoulos, A., … Wong, S. S. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. British Journal of Pharmacology, 180(Suppl 2), S289–S373. https://doi.org/10.1111/bph.16181
    1. Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175, 407–411. https://doi.org/10.1111/bph.14112
    1. Alleaume‐Butaux, A., Nicot, S., Pietri, M., Baudry, A., Dakowski, C., Tixador, P., Ardila‐Osorio, H., Haeberlé, A. M., Bailly, Y., Peyrin, J. M., Launay, J. M., Kellermann, O., & Schneider, B. (2015). Double‐edge sword of sustained ROCK activation in prion diseases through Neuritogenesis defects and prion accumulation. PLoS Pathogens, 11, e1005073. https://doi.org/10.1371/journal.ppat.1005073
    1. Baglietto‐Vargas, D., Medeiros, R., Martinez‐Coria, H., LaFerla, F. M., & Green, K. N. (2013). Mifepristone alters amyloid precursor protein processing to preclude amyloid Beta and Also reduces tau pathology. Biological Psychiatry, 74, 357–366. https://doi.org/10.1016/j.biopsych.2012.12.003