Datta Dibyadeep, Perone Isabella, Wijegunawardana Denethi, Liang Feng, Morozov Yury M, Arellano Jon, Duque Alvaro, Xie Zhongcong, van Dyck Christopher H, Arnsten Amy F T
bioRxiv. 2023 Nov 10:2023.11.07.566046. doi: 10.1101/2023.11.07.566046.
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 brain, as soluble pT217-tau is dephosphorylated postmortem in humans.
We utilized multi-label 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.
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 CSF/blood. Plasma pT217-tau levels increased across the age-span and thus can serve as a biomarker in macaques.
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.
pT217-τ是一种新型的基于体液的生物标志物，可预测阿尔茨海默病（AD）症状的发作，但对于pT217-τ在大脑中如何产生知之甚少，因为可溶性pT217-τ在人类死后会发生去磷酸化。
我们利用多标记免疫荧光和免疫电子显微镜来检查患有自然发生的tau病理的老年猕猴内嗅皮质和前额叶皮质中早期pT217-τ的亚细胞定位，并检测血浆中的pT217-τ水平。
pT217-τ聚集在树突内的微管上，这些树突表现出包括自噬空泡在内的早期退化迹象。在棘突上的突触内的兴奋性神经元之间也可见其运输，在那里它暴露于细胞外空间，因此可进入脑脊液/血液。血浆pT217-τ水平在整个年龄范围内升高，因此可作为猕猴的生物标志物。
这些数据有助于解释为什么pT217-τ可预测AD中的退化以及它如何进入脑脊液和血浆以作为一种体液生物标志物。
