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

ABSTRACT Tau reduction is a promising therapeutic strategy for Alzheimer’s 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. SUMMARY A 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. Competing Interest Statement EDR has received grants from NIH, Bluefield Project to Cure FTD, and the Alzheimers Drug Discovery Foundation and is site PI for clinical trials with Eisai and Lilly. He owns IP related to tau and received royalties from Genentech. He served as an advisor for AGTC, member of a data monitoring committee for Lilly, and member of an Editorial Board for the Society for Neuroscience.