RNAi knockdown of microtubule‐associated protein Tau prevents axonal damage and clears pre‐existing Tau aggregates in P301S transgenic tauopathy model mice

Abstract Background The hyperphosphorylation and subsequent aggregation of the microtubule‐associated protein Tau (encoded by the MAPT gene) is one of the major histopathological hallmarks of numerous tauopathies, including Alzheimer’s disease and progressive supranuclear palsy. The intracellular accumulation of aggregated Tau is associated with neuronal loss and disease progression in tauopathies. There is a high‐unmet need to identify strategies to target the intracellular accumulation of Tau aggregates with the aim of slowing tauopathy progression. Method To model this, we used mice carrying multiple copies of a transgene with a prion promoter driving human MAPT with human tauopathy‐inducing mutation P301S. P301S‐Tau transgenic mice progressively accumulate neuroglial Tau aggregates associated with axonal damage, gliosis, body weight loss, and ambulatory dysfunction. Result P301S mice treated with a single intracerebroventricular injection of Tau siRNA at eight months of age, had a sustainable decrease in MAPT mRNA and soluble Tau protein for three months following siRNA treatment (reduced ∼83% and ∼59%, respectively). siRNA treatment also prevented the progressive decrease in body weight and abrogated axonal damage, evidenced by decreased neurofilament light (NFL) chain in plasma and cerebrospinal fluid of eleven‐month‐old mice. Importantly, immunohistochemical analysis of misfolded Tau in vivo and HEK293‐4RD‐CFP/YFP Tau aggregate biosensor assay testing in vitro revealed a ∼97% decrease of Tau aggregates in the eleven‐month‐old mice, suggesting there exists a yet‐to‐be identified mechanism of Tau fibril clearance. Conclusion Together, these results suggest an RNAi therapeutics approach targeting of MAPT mRNA may be sufficient to improve multiple parameters of tauopathy disease progression and a provide a compelling rationale for further development of Tau‐lowering strategies.