An Early Olfactory Transcriptomic Signature of Tauopathy: Gbp2b Emerges as a Candidate Biomarker of Tau-Driven Neuroinflammation

Olfactory dysfunction is increasingly recognized as an early feature of neurodegenerative diseases such as Alzheimer’s disease. PS19 mice, a well-established tauopathy model, exhibit hallmarks of tau pathology—including hyperphosphorylated tau and pretangle formations—in various regions of the olfactory system. Notably, very recent data demonstrated that aberrantly hyperphosphorylated tau (pTau) was detected as early as 1.5 months of age in the olfactory epithelium (OE). This region contains olfactory sensory neurons projecting to the olfactory bulb (OB), where similar pTau pattern was also observed at this early stage. By 6 months, tau pretangles were evidenced in higher olfactory areas such as the piriform and entorhinal cortices. Given the early involvement of the OE and OB in tau pathology, we performed transcriptomic analyses at 3, 6, and 9 months to investigate the molecular pathways underlying tau pathology in these olfactory regions. Due to the OE’s peripheral location and anatomical accessibility, we also aimed in that respect to identify potential early biomarkers of tauopathy. The hippocampus, a key brain region affected in Alzheimer’s disease and related disorders, was included in the analysis as a comparative reference due to its known vulnerability and clinical relevance. Our analyses revealed region- and age-specific gene expression changes in PS19 mice. Functional enrichment analyses indicated a temporal progression of molecular alterations associated with tau pathology. We identified a subset of genes differentially expressed across different time points and/or regions. Among these, Gbp2b emerged as a particularly promising early biomarker candidate for tauopathy in the OE, showing consistent upregulation across tau pathological stages and brain regions.