this is not the case for the phosphorylation at sites Ser199–202–Thr205. Using the AT8 marker, we found that the total number of structures does Palbociclib not show differences when reaching advanced AD stages, suggesting that at some point during the tau processing this phosphorylation reaches a stable level (Figure 5); conversely PHF-1 during advanced stages remains significantly increased (Figure 5). Again, these data show important differences between events in the carboxyl terminus vs. the middle of the molecule, suggesting that the carboxyl terminus is exposed to phosphorylation events from early to advanced processing stages. To further evaluate the role of phosphorylation of tau protein at sites Ser396–404, we studied the abnormal processing of tau protein in DS. In this study, we found that hyperphosphorylated tau protein
at sites Ser199–202–Thr205 and Ser396–404 is present in the cytopathology found in DS. Here again, PHF-1 detected both early aggregates (iNFT) and mature NFTs (Figure 6), and finally, the density of structures displaying phosphorylation at sites Ser396–404 was significantly increased compared with those phosphorylated at Ser199–202–Thr205 or Ser262 (Figure 6). According to these data, we propose that phosphorylation at Ser396–404 is followed by phosphorylation at sites Ser199–202–Thr205 Erlotinib and possibly some other phosphorylations like Ser262 (Figure 6). However using the same criteria, we cannot rule out the possibility that phosphorylation at site Ser262 is also an early event, mainly due to the fact that most of the structures comprising this event were found in a pretangle like stage (Figure 6). Here, we suggest that abnormal aggregation of this protein, in a different tau disease, is conducted by common mechanisms promoting its hyperphosphorylated state. To further
analyse if processing of tau protein was similar to what we Farnesyltransferase saw during AD, we studied the presence of cleavage events at sites D421 and E391. Some NFT pathology showed a considerable level of cleavage at site D421 and small amount of pathology with of the E391 truncated tau (Figure 6). These data show a clear difference between AD and DS. Tau protein does not seem to reach late stages of abnormal processing during DS (Figure 7). Despite this finding, the presence of E391 truncated tau in DS may suggest that NFTs during DS are exposed to proteolytic events and processed similarly to intracellular NFTs during AD. In sum, like in AD, in DS phosphorylated tau was observed in a nonfibrillar state suggesting again that phosphorylation at the carboxyl terminus could be critically related to the pathogenesis of the disease.