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

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

Department of Pathology and Laboratory Medicine, University of California, 837 Health Sciences Rd., Irvine, CA 92697, USA. · pubmed

Paper

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.

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Research summary

The paper investigates the effects of CN/NFAT inhibitors on cognitive decline in a canine model of Alzheimer's disease, which is relevant to aging and age-related cognitive decline. However, it primarily focuses on symptomatic treatment rather than addressing the root causes of aging or lifespan extension. While the findings are solid and contribute to the understanding of cognitive maintenance in aging, the impact is limited as it does not present a major breakthrough or transformative implications for the field of longevity research.

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