Correlation between tau phosphorylation sites and tangle morphology in Alzheimer's disease

Background:  To study the relationship between phosphorylation sites of the tau protein and changes in the configuration of neurofibrillary tangles (NFT) in brains with Alzheimer's disease (AD). Methods:  Seven brains from patients with non-familial AD and three control brains were examined. NFT were immunolabeled with five monoclonal antibodies against phosphorylated serine (pSer) and threonine (pThr): AT180 targets pThr231; AT8 targets pSer202 and pThr205; HT7 targets pSer159–163; Tau2 targets pSer101; and Tau5 targets the central region of the tau sequence. Tau-labeled NFT (tNFT) were grouped into pretangles (p-NFT), intracellular tangles (i-NFT) and extracellular ghost tangles (e-NFT) according to their cytological features. Gallyas-stained NFT (gNFT) were regarded as the NFT population of AD. The cerebral regions examined included the cornu ammonis (CA), entorhinal cortex, anterior cingulate cortex, inferior parietal lobe, temporal neocortex, occipital cortex and lateral prefrontal lobe. The first three regions were grouped into the limbic cortex and the others into the association cortex. Results:  p-NFT were observed with all tau labeling, with the p-NFT/tNFT percentage ranging from 14% to 19%, and densities of p-NFT and i-NFT were higher in the limbic cortex than in the association cortex. The p-NFT/tNFT ratio in Tau2 labeling was the lowest compared with the other tau labeling. e-NFT showed an irregular density distribution across both cerebral regions and different tau labeling, and the densities of p-NFT and e-NFT were correlated with that of tNFT. In contrast, e-NFT were correlated with p-NFT in AT180 and Tau5 labeling. Conclusion:  The higher densities of p-NFT and i-NFT in the limbic cortex compared to the association cortex are compatible with the regional extension of NFT. pSer101 is closely associated with the late process of p-NFT generation, and pSer202 and pThr205 are presumed to be triggers for the generation of p-NFT. Phosphorylation of pSer101 detected by Tau2 plays an important role in the formation of e-NFT and p-NFT.