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

Abstract

Background and Purpose: Exposure to chronic stress and high levels of glucocorticoid 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