Abstract
The role of Tau phosphorylation in neurofibrillary degeneration linked to Alzheimer's disease remains to be established. While transgenic mice based on FTDP-17 Tau mutations recapitulate hallmarks of neurofibrillary degeneration, cell models could be helpful for exploratory studies on molecular mechanisms underlying Tau pathology. Here, “human neuronal cell lines” overexpressing Wild Type or mutated Tau were established. Two-dimensional electrophoresis highlights that mutated Tau displayed a specific phosphorylation pattern, which occurs in parallel to the formation of Tau clusters as visualized by electron microscopy. In fact, this pattern is also displayed before Tau pathology onset in a well established mouse model relevant to Tau aggregation in Alzheimer's disease. This study suggests first that pathological Tau mutations may change the distribution of phosphate groups. Secondly, it is possible that this molecular event could be one of the first Tau modifications in the neurofibrillary degenerative process, as this phenomenon appears prior to Tau pathology in an in vivo model and is linked to early steps of Tau nucleation in Tau mutants cell lines. Such cell lines consist in suitable and evolving models to investigate additional factors involved in molecular pathways leading to whole Tau aggregation.
Highlights
The discovery of Tau mutations associated with Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), has allowed for generating several animal models and especially Tau transgenic mice that display a Tau pathology characterized by abnormal phosphorylation and Tau aggregation [1,2,3,4,5,6]; and for review [7]
Overall Tau phosphorylation analysis in transgenic mice To analyse relevance of the findings described above, 2D analysis of Tau was performed in a recent characterized transgenic mouse model relevant to Tau pathology in Alzheimer’s disease [1]
Electron microscopy analysis in our cell models showed no Tau aggregates similar to those observed in transgenic mice models or pathological human brains
Summary
Tau (tubulin associated unit) is a microtubule-associated protein. In the human brain, there are six Tau isoforms generated by alternative splicing. Analysis of overall Tau phosphorylation by 2D analysis followed by immunoblots with antibodies directed against Total exogenous human Tau revealed the presence of Tau isovariants in a pI range with high molecular weight levels (L2 and L3) consistent with the pattern observed for mutated Tau in SH-SY5Y cell lines (Fig. 3). This analysis performed in brains of 3 weeks old mice suggest that this molecular event appears very early in the degeneration process. Neverthelesss, as reported in previous cellular models, these structures are still far different from the main typical Tau aggregates found in Tauopathies since they are neither straight nor paired helical filaments
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