Abstract
Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets.
Highlights
Alzheimer’s disease (AD) is neuropathologically characterized by two hallmark lesions, which are extracellular amyloid-β (Aβ) plaques and intracellular accumulations of abnormally phosphorylated tau
The present study aims to evaluate the spatial and temporal phosphorylation profile of different tau sites by applying rater-independent automated quantification based on digital image analysis
Since tau phosphorylation is a main characteristic of AD progression, several groups have already analyzed the temporal phosphorylation pattern of different tau sites by histological methods
Summary
Alzheimer’s disease (AD) is neuropathologically characterized by two hallmark lesions, which are extracellular amyloid-β (Aβ) plaques and intracellular accumulations of abnormally phosphorylated tau. Tau pathology manifests as neurofibrillary tangles (NFTs) and neuropil threads (NTs) and primarily accumulates in the entorhinal region and subsequently progresses to the limbic system and Neddens et al Acta Neuropathologica Communications (2018) 6:52 phosphorylated in healthy brains [10, 15, 22, 26, 28]. Several of these ptau sites are phosphorylated in the fetal brain and are associated with embryonic brain developmental processes [10, 15, 22]. The phosphorylation profile of other ptau sites known to be involved in AD pathology is so far strongly neglected and analyzed only by ELISA and dot blots of AD brain tissue [20, 46]
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