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

Research output: Contribution to journalArticlepeer-review

3 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 languageEnglish
Pages (from-to)5124-5133
Number of pages10
JournalJournal of Neuroscience
Volume41
Issue number23
DOIs
StatePublished - 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and E.H. designed research; M.F.U., S.M.K., K.B., J.L.M., E.D.J., B.M., and J.S. performed research; L.G.P. contributed unpublished reagents/analytic tools; H.R. and C.E.L.S. analyzed data; H.R., C.E.L.S., and E.H. wrote the paper.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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