Hyperphosphorylation of Tau at Ser396 occurs in the much earlier stage than appearance of learning and memory disorders in 5XFAD mice.

The present study investigated the relation of age-dependent spatial learning/memory impairment and Tau phosphorylation in 5XFAD mice, a model of Alzheimer's disease. In the water maze test, the acquisition and retention latencies for 5XFAD mice at 6 months, but not 2 months, of age was significantly longer than those for wild-type mice at the same months of age, without difference in the swim speed and visual acuity between two groups. The level of glycogen synthase kinase 3β (GSK-3β) phosphorylation at Ser9 in the hippocampus for the 5XFAD mice at >4 months of age was significantly lesser than that for wild-type mice at the same months of age, while a robust increase in the Tyr216 phosphorylation of GSK-3β was found both in wild-type and 5XFAD mice at 6 months of age, without no significant difference in the extent between two groups. There was no significant difference in the Tau phosphorylation at Ser202/Thr205 in the hippocampus between two groups, but Ser396 phosphorylation for 5XFAD mice was significantly higher than that for wild-type mice at ages ranging from 2 to 6 months. The results of the present study indicate that Tau hyperphosphorylation in the brain for 5XFAD mice precedes high activation of GSK-3β and occurs in the much earlier stage than appearance of learning and memory disorders.