Capillary Plasma GFAP and NfL Track In Vivo Tauopathy Progression in PS19 Mice

Background Alzheimer’s disease (AD) is characterized by progressive tau pathology and neurodegeneration. While blood-based biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau at threonine 181 (p-Tau181) are increasingly utilized for detecting these pathological processes, conventional venous blood sampling poses limitations for frequent and decentralized monitoring. This study aimed to evaluate the utility of capillary blood and skin interstitial fluid (ISF) as minimally invasive matrices for monitoring tau-related pathology in a tauopathy mouse model. Methods Microdialysis-based ISF collection was first optimized in C57BL/6J mice to confirm protein recovery and minimize blood contamination. Venous plasma, capillary plasma, and ISF were subsequently collected from PS19 tauopathy mice (n = 29) and wild-type mice (n = 17) at defined disease stages (4–12 months of age). Concentrations of GFAP, NfL, and p-Tau181 were quantified using the Simoa platform. Tau pathology was assessed by AT8 immunohistochemistry. Statistical analyses included Spearman correlation, linear regression, and receiver operating characteristic (ROC) curve analysis. Results In PS19 mice, both venous and capillary plasma concentrations of GFAP and NfL significantly correlated with brain tau pathology scores (p < 0.0001). Capillary plasma levels closely mirrored venous concentrations, with strong cross-matrix correlations. In contrast, p-Tau181 levels did not consistently correlate with pathological burden in either matrix. ISF levels of all biomarkers showed no significant correlation with brain pathology or plasma levels, likely due to technical limitations of microdialysis and the inherently low protein concentration in ISF. Conclusions Capillary blood–derived GFAP and NfL reliably reflect tau-related neurodegeneration in PS19 mice and represent promising minimally invasive biomarkers suitable for longitudinal and translational research. In contrast, current ISF sampling approaches are insufficient for AD biomarker detection and require further methodological refinement.