Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology

Neuronal protein inclusions are a common feature in Alzheimer disease (AD) and Pick disease. Even though the inclusions are morphologically different, flame-shape structure for AD vs. spherical structure for Pick disease, both have filaments mainly composed of tau protein. In AD, a well-defined pattern of conformational changes and truncation has been described. In this study, we used laser scanning confocal microscopy to characterize and compare the processing of tau protein during Pick disease with that found in AD. We found that tau protein of Pick disease preserves most of the relevant epitopes found in AD, the conformational foldings labelled by Alz-50 and Tau-66, the cleavage sites D(421) and E(391), as well as many phosphorylated sites, such as Ser(199/202), Thr(205) and Ser(396/404). We found a strong pattern of association between phosphorylation and cleavage at site D(421), as well as the phosphorylation and the conformational Alz-50 epitope. When we used late AD markers such as the conformational Tau-66 epitope and MN423 (cleavage at site E(391)) in Pick bodies (PBs), the overlap was significantly less. Furthermore, following morphological quantification, we found significantly higher numbers of phosphorylated tau in PBs. Overall, our findings suggest that phosphorylation is an early event, likely preceding the cleavage of tau at D(421). Despite this consistency with AD, we found a major distinction, namely that PBs lack beta-sheet conformation. We propose a scheme of early tau processing in these structures, similar to neurofibrillary tangles of AD.