Abstract
<title>Abstract</title> <p>Progressive Supranuclear Palsy (PSP) is a 4-repeat tauopathy characterized by the regional progression of tau pathology, which may be mediated by neurotoxic oligomeric forms of aggregated misfolded tau protein that preceded mature fibrillar aggregates. We evaluated the performance of pTP-TFE, a novel small-molecule fluorescent probe designed to selectively bind soluble tau oligomers, compared to the standard phosphorylated tau antibody AT8. Using quantitative fluorescence and confocal imaging across four neuropathologically confirmed PSP cases, we mapped the tau burden in the globus pallidus (GP), frontal cortex (FC), and occipital cortex (OC). Both pTP-TFE and AT8 revealed a consistent regional gradient (GP > FC > OC). Critically, pTP-TFE exhibited significantly enhanced sensitivity in the occipital cortex detecting tau-positive signal where AT8 immunoreactivity was minimal (% Area: p = 0.03; Raw Integrated Density: p = 0.04). Regression analysis confirmed a strong correlation between pTP-TFE and AT8 (r = 0.925) but yielded a distinct positive y-intercept, indicating that pTP-TFE detects residual tau species independent of phosphorylation. Punctua colocalization of AT8 and pTP-TFE support a non-reciprocal relationship in which most AT8-positive structures are pTP-TFE-positive, whereas a substantial subset of pTP-TFE-positive structures lack AT8 signal. We conclude that pTP-TFE identifies a pool of widely distributed oligomeric tau that precedes mature aggregates, highlighting its potential as a sensitive tool for early diagnosis and for monitoring at the leading edge of PSP progression.</p>