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 D421 and E391, as well as many phosphorylated sites, such as Ser199/202, Thr205 and Ser396/404. We found a strong pattern of association between phosphorylation and cleavage at site D421, 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 E391) 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 D421. Despite this consistency with AD, we found a major distinction, namely that PBs lack β‐sheet conformation. We propose a scheme of early tau processing in these structures, similar to neurofibrillary tangles of AD.