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

doi:10.1016/j.neurobiolaging.2024.11.003

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1-14
Number of pages	14
Journal	Neurobiology of Aging
Volume	146
DOIs	https://doi.org/10.1016/j.neurobiolaging.2024.11.003
State	Published - Feb 2025

Bibliographical note

Publisher Copyright:
© 2024 Elsevier Inc.

Keywords

Alzheimer disease
Beagle
Cognition
Preclinical prevention study
Q134R
Tacrolimus

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neurobiolaging.2024.11.003

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Sordo, L., Ubele, M. F., Boaz, K. A., Mefford, J. L., Jones, E. D., McCarty, K. L., van Rooyen, H. Y., Smiley, J., Bembenek Bailey, S. A., Perpich, J. A., Meacham, B., Powell, D. K., Bresch, F., Crump, J. W., Phelan, M. J., Noche, J. A., Stark, C. E., Puskás, L. G., Norris, C. M., & Head, E. (2025). Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease. Neurobiology of Aging, 146, 1-14. https://doi.org/10.1016/j.neurobiolaging.2024.11.003

@article{49d2f8c224cd4990ba639e185ca62cc3,

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

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.",

keywords = "Alzheimer disease, Beagle, Cognition, Preclinical prevention study, Q134R, Tacrolimus",

author = "Lorena Sordo and Ubele, {Margo F.} and Boaz, {Kathy A.} and Mefford, {Jennifer L.} and Jones, {Erin Dehnart} and McCarty, {Katie L.} and {van Rooyen}, {Hollie Y.} and Jeffrey Smiley and {Bembenek Bailey}, {Stasia A.} and Perpich, {Jessica A.} and Beverly Meacham and Powell, {David K.} and Frederick Bresch and Crump, {Jacob W.} and Phelan, {Michael J.} and Noche, {Jessica A.} and Stark, {Craig E.} and Pusk{\'a}s, {L{\'a}szl{\'o} G.} and Norris, {Christopher M.} and Elizabeth Head",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2025",

month = feb,

doi = "10.1016/j.neurobiolaging.2024.11.003",

language = "English",

volume = "146",

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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 & Head, E 2025, 'Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease', Neurobiology of Aging, vol. 146, pp. 1-14. https://doi.org/10.1016/j.neurobiolaging.2024.11.003

TY - JOUR

T1 - Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease

AU - Sordo, Lorena

AU - Ubele, Margo F.

AU - Boaz, Kathy A.

AU - Mefford, Jennifer L.

AU - Jones, Erin Dehnart

AU - McCarty, Katie L.

AU - van Rooyen, Hollie Y.

AU - Smiley, Jeffrey

AU - Bembenek Bailey, Stasia A.

AU - Perpich, Jessica A.

AU - Meacham, Beverly

AU - Powell, David K.

AU - Bresch, Frederick

AU - Crump, Jacob W.

AU - Phelan, Michael J.

AU - Noche, Jessica A.

AU - Stark, Craig E.

AU - Puskás, László G.

AU - Norris, Christopher M.

AU - Head, Elizabeth

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

KW - Alzheimer disease

KW - Beagle

KW - Cognition

KW - Preclinical prevention study

KW - Q134R

KW - Tacrolimus

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UR - http://www.scopus.com/inward/citedby.url?scp=85208974580&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2024.11.003

DO - 10.1016/j.neurobiolaging.2024.11.003

M3 - Article

C2 - 39547056

AN - SCOPUS:85208974580

SN - 0197-4580

VL - 146

SP - 1

EP - 14

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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