Creed, R. B. | Search bioRxiv

bioRxiv2024

Tau P301S Transgenic Mice Develop Gait and Eye Movement Impairments That Mimic Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with an estimated prevalence of 5-7 people in 100,000. Clinically characterized by impairments in gait, balance, and eye movements, as well as aggregated Tau pathology, PSP leads to death in approximately 5-8 years. No disease-modifying treatments are currently available. The contribution of Tau pathology to the symptoms of patients with PSP is poorly understood, in part due to lack of a rodent model that recapitulates characteristic aspects of PSP. Here, we assessed the hTau.P301S mouse for key clinical features of PSP, finding progressive impairments in balance and gait coordination. Additionally, we found impairments in fast vertical eye movements, one of the most distinctive features of PSP. Across animals, we found that Tau pathology in motor control regions correlated with motor deficits. These findings highlight the utility of the hP301S mouse in modeling key aspects of PSP.

neuroscience↗

bioRxiv2024

Excitoprotective effects of conditional tau reduction in excitatory neurons and in adulthood

Tau reduction is a promising therapeutic strategy for Alzheimers disease. In numerous models, tau reduction via genetic knockout is beneficial, at least in part due to protection against hyperexcitability and seizures, but the underlying mechanisms are unclear. Here we describe the generation and initial study of a new conditional Tauflox model to address these mechanisms. Given the protective effects of tau reduction against hyperexcitability, we compared the effects of selective tau reduction in excitatory or inhibitory neurons. Tau reduction in excitatory neurons mimicked the protective effects of global tau reduction, while tau reduction in inhibitory neurons had the opposite effect and increased seizure susceptibility. Since most prior studies used knockout mice lacking tau throughout development, we crossed Tauflox mice with inducible Cre mice and found beneficial effects of tau reduction in adulthood. Our findings support the effectiveness of tau reduction in adulthood and indicate that excitatory neurons may be a key site for its excitoprotective effects. SUMMARYA new conditional tau knockout model was generated to study the protective effects of tau reduction against hyperexcitability. Conditional tau reduction in excitatory, but not inhibitory, neurons was excitoprotective, and induced tau reduction in adulthood was excitoprotective without adverse effects.

neuroscience↗