Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease

Authors

• Lorena Sordo, University of California, Irvine
• Margo F. Ubele, University of KentuckyFollow
• Kathy Boaz, University of KentuckyFollow
• Jennifer L. Mefford, University of Kentucky
• Erin Dehnart Jones, University of Kentucky
• Katie L. McCarty, University of KentuckyFollow
• Hollie Y. van Rooyen, University of Kentucky
• Jeffrey R. Smiley, University of KentuckyFollow
• Stasia A. Bembenek Bailey, University of Kentucky
• Jessica A. Perpich, University of Kentucky
• Beverly Meacham, University of Kentucky
• David K. Powell, University of KentuckyFollow
• Frederick Bresch, University of Kentucky
• Jacob W. Crump, University of Kentucky
• Michael J. Phelan, University of California, Irvine
• Jessica A. Noche, University of California, Irvine
• Craig E. Stark, University of California, Irvine
• László G. Puskás, Aperus Pharma, Hungary
• Christopher M. Norris, University of KentuckyFollow
• Elizabeth Head, University of California, IrvineFollow

Abstract

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern of cognitive maintenance and duration of their effect, there was improvement in spatial learning, as well as maintenance of memory, attention, and working memory relative to placebo dogs. CN/NFAT inhibition is a promising target for prevention of cognitive decline that may be rapidly implemented in human clinical trials.

Document Type

Article

Publication Date

2025

Notes/Citation Information

0197-4580/© 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.neurobiolaging.2024.11.003

Funding Information

This study was supported by NIH/NIA R01AG056998 and RF1AG056998 to EH and CN.

Repository Citation

Sordo, Lorena; Ubele, Margo F.; Boaz, Kathy; Mefford, Jennifer L.; Jones, Erin Dehnart; McCarty, Katie L.; van Rooyen, Hollie Y.; Smiley, Jeffrey R.; Bembenek Bailey, Stasia A.; Perpich, Jessica A.; Meacham, Beverly; Powell, David K.; Bresch, Frederick; Crump, Jacob W.; Phelan, Michael J.; Noche, Jessica A.; Stark, Craig E.; Puskás, László G.; Norris, Christopher M.; and Head, Elizabeth, "Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease" (2025). Pharmacology and Nutritional Sciences Faculty Publications. 137.
https://uknowledge.uky.edu/pharmacol_facpub/137