Truncation of tau and neurodegeneration

Our results suggest that truncation of tau is an early event in AD. We have shown intense granular staining inside neurons which did not exhibit any n eurofibrillary changes. Therefore, we suggest that truncation of tau preced es the formation of tangles. The process of tau truncation is independent o f postmortem delay (tested up to 17 h PMD). It is well documented that neur ons die in AD. To assess the impact of tau truncation on neuronal degenerat ion in AD we employed the ISEL technique, which identifies nuclei with frag mented DNA. In accordance with previous results, we found few or no ISEL-po sitive nuclei in sections from non-demented control brains, while numerous nuclei were labelled in sections from AD brains. MN423/ISEL double-labellin g studies demonstrated that truncation of tau and cell degeneration are cor related. This result, together with our latest data from cellular models, f urther strengthens our working hypothesis that tau truncation precedes cyto skeletal changes related to neurofibrillary pathology. Furthermore, we have shown that tau is an in vivo substrate for proteases during apoptosis. Thu s, the truncation of tau appears to be not only an early but also, together with hyperphosphorylation, the most deleterious event in neuronal degenera tion.