1. Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease.
- Author
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Sordo L, Ubele MF, Boaz KA, Mefford JL, Jones ED, McCarty KL, van Rooyen HY, Smiley J, Bembenek Bailey SA, Perpich JA, Meacham B, Powell DK, Bresch F, Crump JW, Phelan MJ, Noche JA, Stark CE, Puskás LG, Norris CM, and Head E
- Subjects
- Animals, Dogs, Male, Female, Spatial Learning drug effects, Memory drug effects, Cognitive Dysfunction prevention & control, Cognitive Dysfunction etiology, Alzheimer Disease drug therapy, Alzheimer Disease prevention & control, Alzheimer Disease metabolism, Alzheimer Disease psychology, NFATC Transcription Factors metabolism, Disease Models, Animal, Cognition drug effects, Calcineurin Inhibitors pharmacology, Calcineurin Inhibitors therapeutic use, Tacrolimus pharmacology, Tacrolimus therapeutic use, Calcineurin metabolism, Aging psychology, Aging drug effects
- 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., Competing Interests: Declaration of Competing Interest Personal financial interest as LGP is the main shareholder of one of Aperus Pharma Co. Ltd’s company shares., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2025
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