Spatiotemporal transcriptomic profiling reveals metabolic dysfunction prior to overt tauopathy in the PS19 mouse model.

Abnormal accumulation of hyperphosphorylated tau in neurofibrillary tangles is a hallmark of neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia. In AD, tangle pathology characteristically develops in brain regions with heightened vulnerability, such as the entorhinal cortex and hippocampus. Emerging evidence implicates mitochondrial dysfunction and metabolic disturbances in AD progression, yet the relationship between regional vulnerability and pretangle tau-driven transcriptomic changes remains unclear. To address this critical gap, we utilized the tau P301S transgenic mouse model (PS19 line), which develops tau inclusions. Using spatial transcriptomic profiling across the hippocampal and cortical regions at selected disease stages, we captured spatiotemporal transcriptional responses to tauopathy. Our findings reveal that disease-associated microglia and astrocyte phenotypes emerge concurrently with phosphorylated tau accumulation across multiple brain regions. Intriguingly, the expression of