Nanoscale imaging of pT217‐tau in aged rhesus macaque: Trans‐synaptic propagation and seeding of tau pathology in entorhinal cortex

Tau pathology in Alzheimer’s Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to “seed” pathology throughout the neuronal network. Recent discoveries indicate that tau phosphorylated at threonine 217 (pT217‐tau) can be captured in cerebrospinal fluid (CSF) and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixation of monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in layer II ERC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space.