Behavioural Functions and Cerebral Blood Flow in a P301S Tauopathy Mouse Model: A Time-Course Study

Abstract

Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) in neurons and glial cells. PS19 mice bearing the MAPT P301S mutation have been used to mimic human frontotemporal lobar degeneration. The present study was designed to systematically investigate how behavioural functions, resting cerebral blood flow (CBF) and tau pathology change in PS19 mice at 2, 4, 6, 8 and 12 months of age in a single study under one experimental condition, allowing for the cumulative assessment of age- and genotype-dependent changes. PS19 mice displayed hyperactivity and reduced anxiety levels with age, early and persistent spatial working memory deficits and reduced resting neocortical CBF. Immunoblotting and immunohistochemistry revealed age-related increases in phosphorylated tau in the brain of PS19 mice. In conclusion, the present study, for the first time, cumulatively demonstrated the time-course of changes in behavioural functions, resting CBF and tau pathology in a P301S tauopathy mouse model through their developmental span. This information provides further evidence for the utility of this model to study neurodegenerative events associated with tauopathy and tau dysfunction.

Keywords: PS19 mice; anxiety; cerebral blood flow; hippocampus; hyperactivity; spatial learning and memory; tau; tauopathy.

Figure 1

Mean (±SEM) body weights (g) of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months of age (n = 11–15/genotype/age). ^&&&& indicates a significant genotype and age interaction at p < 0.0001. **** indicates a significant genotype effect at p < 0.0001. ^#### indicates a significant age effect at p < 0.0001.

Figure 2

Mean (±SEM) total number of arm entries (A) and time (s) spent in open arms (B) and closed arms (C) of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months of age in the elevated plus maze test (n = 11–15/genotype/age). ^&&&& indicates a significant genotype and age interaction at p < 0.0001. * indicates a significant genotype effect at *** p < 0.001 or **** p < 0.0001. ^##### indicates a significant age effect at p < 0.0001.

Figure 3

Mean (±SEM) path length (m, A) and duration of rearings (B) of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months of age in the open field test (n = 11–15/genotype/age). ^&& indicates a significant genotype and age interaction at p < 0.01. * indicates a significant genotype effect at * p < 0.05 or **** p < 0.0001. ^## indicates a significant age effect at p < 0.01.

Figure 4

Mean (±SEM) total number of arm entries (A) and percentage of spontaneous alternation (B) of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months of age in the Y-maze test (n = 11–15/genotype/age). ^&&& indicates a significant genotype and age interaction at p < 0.001. * indicates a significant genotype effect at *** p < 0.001 or **** p < 0.0001. ^# indicates a significant age effect at ^# p < 0.05 or ^#### p < 0.0001.

Figure 5

Mean (±SEM) path length (m, A–C) and percentage of path length in the outer zone (B) of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months of age in the swim test (A); cued navigation trial (B; visible platform) and place navigation trials (C,D; hidden platform) of the water maze test (n = 11–15/genotype/age). * indicates a significant genotype effect at ** p < 0.01 or **** p < 0.0001. ^# indicates a significant age effect at ^# p < 0.05 or ^##### p < 0.0001.

Figure 6

Mean (±SEM) resting cerebral blood flow (CBF) in the neocortex (presented as perfusion unit, PU) of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months of age (n = 11–15/genotype/age). **** indicates a significant genotype effect at p < 0.0001. ^##### indicates a significant age effect at p < 0.0001.

Figure 7

Mean (±SEM) protein levels of phosphorylated tau species Ser202/Thr205 (AT8; A), Ser396 (PHF13; B) and Thr212/Ser214 (AT100; C) in the hippocampus of male wild-type (WT) and PS19 mice at 2, 4, 6, 8 and 12 months (mo) of age (n = 11–15/genotype/age), with example immunoblots of AT8, PHF13, AT100 and GAPDH (data were normalised by GAPDH). ^&&&& indicates a significant genotype and age interaction at p < 0.0001. **** indicates a significant genotype effect at p < 0.0001. ^##### indicates a significant age effect at p < 0.0001.

Figure 8

Immunohistochemistry with the AT8 antibody showing phosphorylated tau (Ser202/Thr205) in the frontal cortex (FC; A,E,I,M,Q), hippocampus (HP; B,F,J,N,R), entorhinal cortex (EC; C,G,K,O,S) and striatum (ST; D,H,L,P,T) of PS19 mice at 2 (A–D), 4 (E–H), 6 (I–L), 8 (M–P) and 12 (Q–T) months of age. Scale bars: 50 µm for each panel.