Tacrolimus protects against age-associated microstructural changes in the beagle brain

Hamsanandini Radhakrishnan; Margo F. Ubele; Stephanie M. Krumholz; Kathy Boaz; Jennifer L. Mefford; Erin Denhart Jones; Beverly Meacham; Jeffrey Smiley; László G. Puskás; David K. Powell; Christopher M. Norris; Craig E.L. Stark; Elizabeth Head

doi:10.1523/JNEUROSCI.0361-21.2021

Tacrolimus protects against age-associated microstructural changes in the beagle brain

Hamsanandini Radhakrishnan, Margo F. Ubele, Stephanie M. Krumholz, Kathy Boaz, Jennifer L. Mefford, Erin Denhart Jones, Beverly Meacham, Jeffrey Smiley, László G. Puskás, David K. Powell, Christopher M. Norris, Craig E.L. Stark, Elizabeth Head

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6 Scopus citations

Abstract

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex (p,0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle age.

Original language	English
Pages (from-to)	5124-5133
Number of pages	10
Journal	Journal of Neuroscience
Volume	41
Issue number	23
DOIs	https://doi.org/10.1523/JNEUROSCI.0361-21.2021
State	Published - Jun 9 2021

Bibliographical note

Funding Information:
Received Feb. 12, 2021; revised Apr. 9, 2021; accepted Apr. 16, 2021. Author contributions: D.K.P., C.M.N., and E.H. designed research; M.F.U., S.M.K., K.B., J.L.M., E.D.J., B.M., and J.S. performed research; L.G.P. contributed unpublished reagents/analytic tools; H.R. and C.E.L.S. analyzed data; H.R., C.E.L.S., and E.H. wrote the paper. This study was funded by National Institutes of Health Grant R01-AG-056998, given to E.H. and C.M.N. We thank Aperus Pharma for supporting one arm of the baseline data of the study. We also thank Frederick Bresch at the University of Kentucky for support with the cognitive testing software. The authors declare they have no conflict of interest. Correspondence should be addressed to Elizabeth Head at heade@uci.edu. https://doi.org/10.1523/JNEUROSCI.0361-21.2021 Copyright © 2021 the authors

Publisher Copyright:
© 2021 the authors.

Keywords

Aging
Alzheimer's disease
Calcineurin
Canine
Diffusion-weighted imaging
Neuroinflammation

ASJC Scopus subject areas

Neuroscience (all)

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10.1523/JNEUROSCI.0361-21.2021

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Radhakrishnan, H., Ubele, M. F., Krumholz, S. M., Boaz, K., Mefford, J. L., Jones, E. D., Meacham, B., Smiley, J., Puskás, L. G., Powell, D. K., Norris, C. M., Stark, C. E. L., & Head, E. (2021). Tacrolimus protects against age-associated microstructural changes in the beagle brain. Journal of Neuroscience, 41(23), 5124-5133. https://doi.org/10.1523/JNEUROSCI.0361-21.2021

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abstract = "The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex (p,0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle age.",

keywords = "Aging, Alzheimer's disease, Calcineurin, Canine, Diffusion-weighted imaging, Neuroinflammation",

author = "Hamsanandini Radhakrishnan and Ubele, {Margo F.} and Krumholz, {Stephanie M.} and Kathy Boaz and Mefford, {Jennifer L.} and Jones, {Erin Denhart} and Beverly Meacham and Jeffrey Smiley and Pusk{\'a}s, {L{\'a}szl{\'o} G.} and Powell, {David K.} and Norris, {Christopher M.} and Stark, {Craig E.L.} and Elizabeth Head",

note = "Funding Information: Received Feb. 12, 2021; revised Apr. 9, 2021; accepted Apr. 16, 2021. Author contributions: D.K.P., C.M.N., and E.H. designed research; M.F.U., S.M.K., K.B., J.L.M., E.D.J., B.M., and J.S. performed research; L.G.P. contributed unpublished reagents/analytic tools; H.R. and C.E.L.S. analyzed data; H.R., C.E.L.S., and E.H. wrote the paper. This study was funded by National Institutes of Health Grant R01-AG-056998, given to E.H. and C.M.N. We thank Aperus Pharma for supporting one arm of the baseline data of the study. We also thank Frederick Bresch at the University of Kentucky for support with the cognitive testing software. The authors declare they have no conflict of interest. Correspondence should be addressed to Elizabeth Head at heade@uci.edu. https://doi.org/10.1523/JNEUROSCI.0361-21.2021 Copyright {\textcopyright} 2021 the authors Publisher Copyright: {\textcopyright} 2021 the authors.",

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doi = "10.1523/JNEUROSCI.0361-21.2021",

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AU - Radhakrishnan, Hamsanandini

AU - Ubele, Margo F.

AU - Krumholz, Stephanie M.

AU - Boaz, Kathy

AU - Mefford, Jennifer L.

AU - Jones, Erin Denhart

AU - Meacham, Beverly

AU - Smiley, Jeffrey

AU - Puskás, László G.

AU - Powell, David K.

AU - Norris, Christopher M.

AU - Stark, Craig E.L.

AU - Head, Elizabeth

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N2 - The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex (p,0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle age.

AB - The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (n = 30, male and female). We find that tacrolimus reduces hippocampal (p = 0.001) and parahippocampal (p = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal (p = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex (p,0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administered at middle age.

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KW - Calcineurin

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KW - Diffusion-weighted imaging

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Tacrolimus protects against age-associated microstructural changes in the beagle brain

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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