TY - JOUR
T1 - Tacrolimus protects against age-associated microstructural changes in the beagle brain
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
N1 - Publisher Copyright:
© 2021 the authors.
PY - 2021/6/9
Y1 - 2021/6/9
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.
KW - Aging
KW - Alzheimer's disease
KW - Calcineurin
KW - Canine
KW - Diffusion-weighted imaging
KW - Neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85108026411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108026411&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0361-21.2021
DO - 10.1523/JNEUROSCI.0361-21.2021
M3 - Article
C2 - 33952632
AN - SCOPUS:85108026411
SN - 0270-6474
VL - 41
SP - 5124
EP - 5133
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 23
ER -