P2-128: Linkage between spatial memory disturbance and tau protein in JNPL3 male mice

Transgenic (tg) mouse models expressing tau are increasingly used in the study of pathogenesis for tauopathy. However, the relationship between tau protein expression and memory dysfunction in these tg mouse models remains unclear. To search possible functions in relation to tau protein expression, behavioral phenotypes in JNPL3 mice expressing human P301L mutant tau were investigated. Hemizygous JNPL3 male mice at 13–18 months of age on an in-bred C57BL/6J strain were tested for place learning and memory performance. At this age group, JNPL3 male mice didn't show any sign of motor deficits. Two days after water maze test, cerebral cortex was dissected and analyzed for biochemical studies. Locomotion activity in open field, motor coordination in rotarod, and swimming speed in water maze were not significantly different between tg and non-tg littermates suggesting that the motor activity did not account for the group differences in the Morris water maze. Place learning test in tg (n=17) and non-tg (n=21) mice showed a similar rate of learning performance. However, distribution of error score in the probe test (learning index) after 6 days of training from tg mice was completely different from non-tg mice. Ten mice from tg group performed within the range of non-tg mice in the assessment of spatial learning (well-learned), while other tg mice had learning and memory deficits (not-learned). Biochemical analysis showed that not-learned tg had higher level of soluble tau and tau phosphorylation at specific sites than well-learned tg. Learning index of tg mice was significantly correlated to soluble tau protein levels but not to human tau protein expression. Correlation between the level of sarkosyl insoluble tau and learning index was not observed. These results indicate that the accumulation of soluble phosphorylated tau before NFT formation may lead to learning and memory deficits in JNPL3 male mice. Although interpretation of results from studies of JNPL3 mice can be complicated by the variability in human tau protein levels and onset of motor impairment, JNPL3 male mice can be useful for the study of spatial memory performance.