Tau Spreading Network Mapping via Spatial Transcriptomics in PSP

SUMMARY

# Tau Spreading Network Mapping via Spatial Transcriptomics in PSP ## Background and Rationale Progressive Supranuclear Palsy (PSP) is a devastating tauopathy characterized by selective vulnerability of brainstem and subcortical regions to 4-repeat (4R) tau aggregation. Current understanding of disease progression relies heavily on post-mortem analyses, limiting insights into dynamic spreading mechanisms. This study leverages cutting-edge spatial transcriptomics to map tau pathology spread in re

METHODOLOGY NOTES

Phase 1 (Months 1-2): Generate PSP mouse model using 3-month-old CaMKII-4R-tau transgenic mice (n=60). Perform stereotaxic injection of human 4R-tau PFFs (2μg in 2μL PBS) into substantia nigra and globus pallidus bilaterally under isoflurane anesthesia. Control groups receive PBS injection (n=24). Phase 2 (Months 3-14): Sacrifice cohorts at 1, 3, 6, and 12 months post-injection (n=15 per timepoint). Rapidly extract brains, embed in OCT, and prepare 10μm cryosections for spatial transcriptomics. Process sections using 10x Genomics Visium platform following manufacturer protocols, capturing 6-8 sections per brain spanning injection sites and connected regions. Phase 3 (Months 15-16): Perform immunohistochemistry on adjacent sections using AT8 (phospho-tau), Iba1 (microglia), and NeuN (neurons) antibodies. Quantify tau burden and cellular densities in regions-of-interest. Phase 4 (Months 17-20): Analyze spatial transcriptomic data using Space Ranger and Seurat pipelines. Identify differen