Pathogenesis of the tauopathies.
ABSTRACT Microtubule-associated protein tau is the most commonly misfolded protein in human neurodegenerative diseases, where it becomes hyperphosphorylated and filamentous. Mutations in MAPT, the tau gene, cause approximately 5% of cases of frontotemporal dementia. They are frequently accompanied by parkinsonism. The existence of MAPT mutations has established that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. However, most tauopathies are not inherited in a dominant manner. The hyperphosphorylated sites are similar between diseases, but filament morphologies and tau isoform compositions vary. This is consistent with the existence of multiple tau conformers and recent findings have provided experimental support for this concept.
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ABSTRACT: The peptide drug candidate NAP (davunetide) has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration. NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death. Recent studies suggest that caspases may play a role in tau pathology. The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system. Our experimental setup used primary neuronal cultures subjected to oxygen-glucose deprivation (OGD), with and without NAP or caspase inhibitor. Cell viability was assessed by measuring mitochondrial activity (MTS assay), and immunoblots were used for analyzing protein level. It was shown that apoptosis was responsible for all cell death occurring following ischemia, and NAP treatment showed a concentration-dependent protection from cell death. Ischemia caused an increase in the levels of active caspase-3 and hyperphosphorylated tau, both of which were prevented by either NAP or caspase-inhibitor treatment. Our data suggest that, in this model system, caspase activation may be an upstream event to tau hyperphosphorylation, although additional studies will be required to fully elucidate the cascade of events.International journal of Alzheimer's disease. 01/2012; 2012:493670.