# Spatiotemporal transcriptomic profiling reveals upregulation of glycolysis pathway genes before overt tauopathy in the PS19 mouse model

## TL;DR

This study finds that changes in brain metabolism happen before visible tau tangle formation in a mouse model of Alzheimer's disease.

## Contribution

The study identifies early metabolic gene changes in vulnerable brain regions before tau pathology onset using spatial transcriptomics.

## Key findings

- Glycolysis pathway genes, including Pgk1, are upregulated in the hippocampus before tau tangle formation.
- Early metabolic changes in the CA3 region correlate with later tangle severity in the PS19 mouse model.
- Spatial transcriptomics reveals region-specific and time-dependent gene expression patterns in tauopathy progression.

## Abstract

The 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. Here, 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 2 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.

This study explores how tau protein buildup affects the brain, particularly in diseases such as Alzheimer’s. Tau proteins can form tangles inside neurons, leading to brain cell damage. Here researchers used a special technique called spatial transcriptomics to examine changes in gene expression in a mouse model with tau pathology, known as PS19 mice. They focused on the hippocampus and cortex, key brain areas involved in memory and cognition. The study found that even before visible tau tangles appeared, there were significant changes in gene activity related to energy metabolism in the hippocampus, especially in a region called CA3. The researchers also observed increased activity of genes involved in glycolysis, highlighting an early marker of tau-related brain changes. This research provides insights into early molecular changes in tauopathies and suggests that targeting metabolic pathways could be a strategy for future treatments.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.