A novel DYRK1a inhibitor, DYR533, reduces tau pathology and TNF alpha in the 3xTg‐AD and PS19 mouse models

Abstract

AbstractBackgroundDual specificity tyrosine phosphorylation kinase 1a (DYRK1a) directly phosphorylates tau and amyloid precursor protein and is upregulated in postmortem brain tissue of patients with disorders including Alzheimer’s (AD) and Picks disease (a tauopathy). Our lab has shown that treatment with a DYRK1a inhibitor (DYR219) reduced Aβ plaque deposition and decreased phosphorylated tau at Serine 396 (pTauSer396) in the 3xTg‐AD mouse model. Here, we developed and tested a novel DYRK1a inhibitor (DYR533), which has an increased half‐life and bioavailability, in 3xTg‐AD mice that develop both Aβ and pathological tau, and PS19 mice that develop solely pathological tau.MethodWe dosed eight‐month‐old 3xTg‐AD and four‐month‐old PS19 mice daily with either 1.0‐, 2.5‐, or 5.0‐mg/kg DYR533 or a vehicle dose for two or four months respectively per model. Treatment start age occurred at the onset of neuropathology. Mice underwent rotarod testing to assess motor function and water maze testing to assess spatial learning and memory, with testing starting 2 weeks prior to the end of treatment. Blood and brain tissue were collected for neuropathology assessment. We assessed Aβ 40‐42 in the 3xTg‐AD mice, and pTauSer396 and the pro‐inflammatory cytokine tumor necrosis factor (Tnf)α in the hippocampus of both models. Blood plasma was extracted and analyzed for Tnfα levels.ResultIn both 3xTg‐AD and PS19 mice, DYR533 reduced soluble and insoluble fractions of pTau Ser396 in a dose dependent manner. Notably, DYR533 in 3xTg‐AD mice reduced pTau at threonine 217, which was recently identified as an early marker of AD progression. Soluble cortical Aβ42 levels were significantly reduced in the 1.0 mg/kg and 5.0 mg/kg 3xTg‐AD groups. DYR533 significantly reduced the levels of Tnfα in blood plasma and the hippocampus of both 3xTg‐AD and PS19 mice.ConclusionIn conclusion, the DYRK1a inhibitor, DYR533, reduces pTauSer396, as well as blood plasma and hippocampal levels of Tnf α in both 3xTg‐AD and PS19 models. Ongoing efforts include testing the effects of DYR533 in a rodent model of Down syndrome (Ts65Dn), which harbors three copies of DYRK1a, and completion of 3xTg‐AD and PS19 experiments. Thus far, these results support DYR533 as a potential therapeutic for AD and the tauopathies.