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 Pgk1, a hub gene of the glycolytic pathway, was upregulated along with other metabolic pathway genes in the CA3 region at 2 months of age, preceding the onset of detectable tau tangle pathology, and correlated with tangle severity, suggesting early metabolic dysregulation in vulnerable regions. Further analysis of differentially expressed genes uncovered region-specific and temporally dynamic transcriptional patterns in the cortex and hippocampus. Early saturable alterations in ATP metabolic processes, glycolysis, and oxidative phosphorylation appeared in the hippocampus at two months of age, with delayed engagement in the cortical regions. These results underscore the contributions of metabolic stress and glial activation to tauopathy and regional vulnerability, highlighting spatial transcriptomics as a powerful tool for uncovering region-specific molecular insights into disease mechanisms.