Background: In the context of pathological aging and Alzheimer's disease (AD), the overexpression of calcineurin has been identified as a factor linked to astrocyte reactivity, neuronal death, and inflammation. This suggests that inhibiting calcineurin or downstream nuclear factor of activated T cells (NFAT) signaling could be a promising strategy for preventing or slowing down AD pathophysiology.
Method: Baseline and annual MRI sessions including higher‐order diffusion‐weighted imaging was performed over four years on 43 dogs ranging from 5 to 8.
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.
View Article and Find Full Text PDFAging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments.
View Article and Find Full Text PDFThe 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 ( = 30, male and female). We find that tacrolimus reduces hippocampal ( = 0.
View Article and Find Full Text PDF