Astrogliosis in Tg(MAPT*P301S+/+) Mice Increases in the Hindbrain at 24 Weeks of Age eFigure 7. Develop Minimal Tau Neuropathology by 24 Weeks of Age eFigure 11. Astrogliosis Does Not Increase in Tg(MAPT*P301S+/?) Mice by 24 Weeks of Age eTable. Power Analysis Determination of Sample Size Needed CIT to Detect Significant Extension in Survival jamaneurol-74-1464-s001.pdf (1.3M) GUID:?D32B0209-245C-4E38-B3AF-0F81347BDCF4 Key Points Question What is a reproducible baseline measure of disease progression in a tauopathy animal model that we can use to determine compound efficacy in drug discovery programs? Findings A total of 1035 mice were used in this time course study. In 1 line of transgenic mice, tau prions were reproducibly detected by age 5 weeks, while considerable variability in another mouse collection renders the model unusable for efficacy studies. Meaning Future studies assessing the ability of small molecules or other therapeutic strategies to slow or halt neurodegeneration should directly measure the ability of the compound to halt tau prion formation in an animal model that exhibits consistent disease kinetics. Abstract Importance Accumulation of the protein tau is usually a defining characteristic of several neurodegenerative diseases. Thorough assessment of transgenic (Tg) mouse lines that replicate this process is critical for establishing the models utilized for screening anti-tau therapeutics in vivo. Objective To define a consistent mouse model of disease for use in future compound efficacy studies. Design, Setting, and Participants In this time course study, cohorts of Tg and control mice were euthanized at defined intervals. Collected brains were bisected down the midline. One half was frozen and used to measure the tau prion content, while the other half was fixed for immunostaining with anti-tau antibodies. All mice were maintained at the Hunters Point Animal Facility at the University or college of California, San Francisco, and all experiments were performed at the Mission Bay Campus of the University or college of California, San Francisco. Study animals were PS19, homozygous and hemizygous Tg(MAPT*P301S), and B6/J mice. The study dates were August 9, 2010, to October 3, 2016. Main Outcomes and AS-605240 Steps Tau prions were measured using a cell-based assay. Neuropathology was measured by determining the percentage area positive for immunostaining in defined brain regions. A separate cohort of mice was aged until each mouse developed neurological indicators as determined by trained animal professionals to assess mortality. Results A total of 1035 mice were used in this time course study. These included PS19 mice (51.2% [126 of 246] male and 48.8% [120 of 246] female), Tg(MAPT*P301S+/+) mice (52.3% [216 of 413] male, 43.8% [181 of 413] female, and 3.9% [16 of 413] undetermined), Tg(MAPT*P301S+/?) mice (51.8% [101 of AS-605240 195] male and 48.2% [94 of 195] female), and B6/J mice (49.7% [90 of 181] male and 50.3% [91 of 181] female). While considerable interanimal variability in neuropathology, disease onset, and tau prion formation in the PS19 mice AS-605240 was observed, all 3 steps of disease were more uniform in the Tg(MAPT*P301S+/+) mice. Comparing tau prion formation in Tg(MAPT*P301S+/+) mice with B6/J controls, the 95% CIs for the 2 2 mouse lines diverged before age 5 weeks, and significant (test. Results A total of 1035 mice were used in this time course study. These included PS19 mice (51.2% [126 of 246] male and 48.8% [120 of 246] female), Tg(MAPT*P301S+/+) mice (52.3% [216 of 413] male, 43.8% [181 of 413] female, and 3.9% [16 of 413] undetermined), Tg(MAPT*P301S+/?) mice (51.8% [101 of 195] male and 48.2% [94 of 195] female), and B6/J mice (49.7% [90 of 181] male and 50.3% [91 of 181] female). Variability of Tauopathy Progression in PS19 Mice Two-month-old PS19 mice were inoculated intracranially with 30 L of either 1??DPBS or 1% control brain homogenate diluted in 5% bovine serum albumin. The mice were collected at age 31 weeks, and the formalin-fixed brains were assessed for tau neuropathology using the antibody AT8 (phosphorylated tau at Ser202/Thr205) (eFigure 1A in the Product). Studies of central nervous system disease proved infeasible due to random variations in tau neuropathology. In a separate group of mice used to assess disease onset, shown.
