Abstract
Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimer’s disease (AD), but the specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (Aβ) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of Aβ plaque load.
Highlights
Tau is a microtubule-associated protein crucial for the stabilization of the neuronal cytoskeleton
Since the vesicles were distributed in a pattern resembling granulovacuolar degeneration bodies (GVB), we stained against p-tau217 together with the GVB marker Ckid [8]
Our study shows that p-tau217 can be found within neurofibrillary tangles (NFTs) and neuropil threads (NT) containing the p-tau variants p-tau181, 231, 202, 202/205, and 369/404, a finding suggesting that phosphorylation of tau at site Thr217 often occurs at the same time as phosphorylation at other tau sites
Summary
Tau is a microtubule-associated protein crucial for the stabilization of the neuronal cytoskeleton. Mis-localization, aggregation, and hyperphosphorylation of the protein are thought to lead to pathological tau spread and neuronal death. This scenario occurs in several different neurodegenerative disorders and aggregated phosphorylated tau (p-tau), forming neurofibrillary tangles (NFT) and neuropil threads (NT), constitutes one of the major neuropathological hallmarks of Alzheimer’s disease (AD). Even more intriguing are reports showing differences in plasma p-tau isoforms in their correlation with tau PET or diagnostic accuracy These findings indicate that the phosphorylation of tau at Thr217 might be related to a subtle and unique aspect of pathology that is different from the other isoforms. We determined whether the p-tau217 load in these brain areas correlates with p-tau217 concentrations in antemortem collected plasma
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