Nanoscale imaging of pT217‐tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early‐stage neurodegeneration

Abstract INTRODUCTION Tau phosphorylated at threonine‐217 (pT217‐tau) is a novel fluid‐based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217‐tau arises in the brain, as soluble pT217‐tau is dephosphorylated post mortem in humans. METHODS We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early‐stage pT217‐tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217‐tau levels in plasma. RESULTS pT217‐tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217‐tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION These data help to explain why pT217‐tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.