Senolytic Intervention in Tauopathy Mice

MAPT P301S PS19 (PS19) mice were purchased from The Jackson Laboratory (stock #008169) and bred to C57BL/6 for three generations. C57BL/6 ATTAC transgenic mice are as described^{3 (link),4 (link)}. Male PS19 mice were bred to ATTAC females to generate cohorts of ATTAC and PS19;ATTAC mice. All mice were on a pure C57BL/6 genetic background. Mice from this cohort were randomly assigned to receive AP20187 (AP; B/B homodimerizer; Clontech) or vehicle twice a week beginning at weaning age (3 weeks). Dosing of AP was 2.0 mg kg^–1 body weight. 6-month-old short-term AP pulse treated animals (Extended Data Fig. 6a) received a dose of 10 mg kg^–1 body weight for 5 consecutive days prior to tissue collection. Senolytic intervention was performed in C57BL/6 WT and PS19 animals. At weaning, mice were assigned to receive either ABT263 (Cayman, 923564–51-6) or vehicle (Phosal 50 PG, Lipoid NC0130871 – 60%; PEG400, Sigma 91893 – 30%, EtOH – 10%). ABT263 was administered by oral gavage at a dose of 50 mg kg^–1 body on a repeating regiment of five consecutive days of treatment followed by 16 days of rest. Animals were housed in a 12h L/D cycle environment in pathogen-free barrier conditions as described in detail^{3 (link)}. Compliance with relevant ethical regulations and all animal procedures were reviewed and approved by the Mayo Clinic Institutional Animal Care and Use Committee.