• TAU is mainly distributed in the central nervous system, most of it exists in the axons of neurons, and a small amount exists in oligodendrocytes. TAU is involved in neurodegenerative diseases, and most prominently in the pathogenesis of Alzheimer disease (AD).
• Gene editing strategy: The exons 2~10 of mouse Mapt gene that encode the full-length protein were replaced by human MAPT exons 2~15 in B-hTAU mice. The 3’UTR region of the mouse gene are replaced by human counterparts. The chimeric MAPT expression is driven by endogenous mouse Mapt promoter, while mouse Mapt gene transcription and translation will be disrupted.
• mRNA expression analysis: Mouse Mapt mRNA was detectable in brain of wild-type C57BL/6 mice. Human MAPT mRNA was detectable in B-hTAU mice.
• Protein expression analysis: Human and mouse TAU was detectable in brain of wild-type mice and homozygous B-hTAU mice.

Strain specific analysis of TAU mRNA expression in wild-type C57BL/6 mice and B-hTAU mice by RT-PCR. Brain RNA were isolated from wild-type C57BL/6 mice (+/+) and homozygous B-hTAU mice (H/H), then cDNA libraries were synthesized by reverse transcription, followed by PCR with mouse or human TAU primers. Human TAU mRNA was detectable only in homozygous B-hTAU mice but not in wild-type mice.

The inhibitory efficiency of the nucleic acid drugs against human TAU in B-hTAU mice. B-hTAU mice were randomly divided into two groups (n=2/group, 6 weeks old, male). The human TAU targeted nucleic acid drugs (from client) and PBS were administered to the mice individually. The mice were sacrificed on day 7, and the brain tissue was collected to detect the human TAU mRNA and protein expression by qRT-PCR and western blot, respectively. (A) The schematic diagram of experimental processing. (B) The expression of human TAU mRNA in brain. The human TAU in the treatment group (G2) was significantly reduced compared to the control group (G1). (C) The expression of human TAU protein in brain. Compared with the control group (G2), the treatment group (G3) showed a significant decrease in hTAU and the inhibition rate in the treatment group was 51.5%, demonstrating that B-hTAU mice provide a powerful preclinical model for in vivo evaluation of human TAU targeted nucleic acid drugs. Values are expressed as mean ± SEM. Validation data was supplied by client.