URSODEOXYCHOLIC ACID FOR THE TREATMENT OF TAUOPATHIES

Abstract

Ursodeoxycholic acid (UDCA) is a bile salt which is currently FDA-approved for the treatment of gallstones, and has also been shown to have neuroprotectant properties in a number of model systems. One of its metabolites, tauroursodeoxycholic acid (TUDCA) has shown neuroprotectant properties in cell culture models of tau neurotoxicity. We evaluated the neuroprotective effects of UDCA in animal models of tau-opathy. In experiment 1, h-tau mice (n=31 males and females) and wild-type C57Bl mice (wt, n= 27 males and 26 females) were fed chow containing 0.4% UDCA or vehicle for 6 weeks, starting at age 16 months. At the end of 6 weeks, spatial memory was tested in Morris Water Maze and then mice were euthanized with terminal harvest of plasma and brain tissue for determination of plasma and brain UDCA and TUDCA levels, as well as brain levels of phosphorylated tau. In experiment 2, PS19 mice were fed chow containing 0.4% UDCA or vehicle beginning at age 3 months and continuing until behavioral testing and sacrifice at age 9 months. Experiment 1: UDCA was well tolerated, with no significant effects on body weight or survival. UDCA treatment was associated with improved Morris Water Maze performance in male h-tau mice (on Probe Test at 72 hours after training, wt mice spent 37% of time in target quadrant, vehicle treated h-tau mice 25%, UDCA treated htau mice 34%). Plasma UDCA = 720±794 ng/ml in UDCA treated mice (n=12) and 33±48 (p=0.006) in vehicle treated mice (n=12). Brain UDCA = 41±50 pg/mg tissue in UDCA treated mice vs 6±1 (p=0.02) for vehicle. Plasma TUDCA = 384±130 ng/ml in UDCA treated mice vs 20±37 (p<0.00001) in vehicle, and brain TUDCA= 7±6 pg/mg tissue in UDCA treated mice vs 0 in vehicle treated mice (p=0.0002). The ratio of hippocampal phosphorylated tau: total tau was reduced in UDCA treated htau mice compared to vehicle-treated mice on Western blot. Experiment 2: Long-term UDCA has been well tolerated in PS19 mice. Analysis of behavior and brain tissue is ongoing. UDCA is well tolerated with chronic treatment, bioavailable, CNS-penetrant, and demonstrated neuroprotectant properties in preliminary studies in mouse models of tau-opathy.