Effect of calcineurin inhibitors on cognition in a canine model of Alzheimer’s disease

Abstract

AbstractBackgroundCalcineurin (CN) is a Ca2+/calmodulin‐dependent phosphatase that regulates diverse cellular phenotypes through activation of NFAT transcription factor1. CN/NFAT signaling increases in Alzheimer’s disease (AD)2,3 and is associated with synaptic loss, neuron degeneration, neuroinflammation, amyloid‐β production, and cognitive decline4,5. Thus, calcineurin inhibitors (CNI) are attractive potential therapeutic to improve cognitive impairments associated with AD.Tacrolimus is an FDA‐approved CNI commonly prescribed for the prophylaxis of solid organ transplant rejection6. In mouse models of AD, tacrolimus ameliorates cognitive deficits7. Moreover, epidemiological studies suggest that tacrolimus reduced the incidence of dementia in kidney transplant patients, when compared to age‐matched controls8.Q134R, a hydroxyquinoline derivative with cytoprotective properties9, inhibits NFAT activity without suppressing CN activity. Q134R improves synapse function and reduce neuroinflammation in AD mouse models10.We hypothesized that chronic low dose tacrolimus and Q134R treatment will prevent cognitive decline over time in middle‐aged beagles, a natural model of human brain aging, amyloid‐β accumulation, and amyloid‐related cognitive impairment.MethodsCognitive outcomes were evaluated in 37 middle‐aged dogs at baseline and during follow‐up (years 1, 2 and 3). Spatial learning and working memory were evaluated using the landmark‐discrimination (1, 2 and 4cm) task and a delayed non‐matching to position (20‐, 70‐, and 110‐second delays) test. Dogs were ranked for cognition at baseline and randomized into one of three treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day PO), and tacrolimus (n = 13; 0.075mg/kg/day PO).ResultsAccuracy at each landmark‐discrimination distance declined significantly among controls faster per year than both treatment groups. Control dogs declined 20% faster than tacrolimus dogs at all distances, and 15% faster than Q134R dogs, at the most difficult distance (4cm).Accuracy on the spatial working memory task declined in each year among controls faster than dogs in the active treatment groups. This effect tended to increase with treatment duration in tacrolimus dogs, whereas it attenuated in Q134R dogs.ConclusionOur findings suggest that both tacrolimus and Q134R have beneficial effects on cognitive outcomes in a canine model of AD, as dogs treated with these compounds showed improved learning, memory, attention, and working memory. Hence, inhibition of the CN pathway may reduce/delay cognitive impairment in AD.