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.
|Number of pages||10|
|Journal||Journal of Neuroscience|
|State||Published - Jun 9 2021|
Bibliographical noteFunding 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and E.H. designed research; M.F.U., S.M.K., K.B., J.L.M., E.D.J., B.M., and J.S. performed research; L.G.P. contributed unpublished reagents/analytic tools; H.R. and C.E.L.S. analyzed data; H.R., C.E.L.S., and E.H. wrote the paper.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 email@example.com. https://doi.org/10.1523/JNEUROSCI.0361-21.2021 Copyright © 2021 the authors
© 2021 the authors.
- Alzheimer's disease
- Diffusion-weighted imaging
ASJC Scopus subject areas
- Neuroscience (all)