The truncated Tau fragment 315-441 produced by Caspase-2 translocates to the nucleus and alters the proteome of neuroblastoma cells.

Alzheimer's disease (AD) symptoms arise from significant loss of neurons in the hippocampal region and the entorhinal cortex. This neuronal death is primarily caused by the abnormal aggregation of Tau protein into paired helical filaments within the somatodendritic compartment. However, the molecular mechanisms underlying this toxicity remain unclear. One contributing factor is the proteolysis of Tau, mainly mediated by Caspase-3. This abnormal post-translational modification promotes Tau aggregation and neuronal toxicity in the brains affected by AD, as well as in vitro cultured cells. Additionally, a new proteolytic site at Asp314, produced by Caspase-2, has been identified in AD. However, little is known about the pathological role of the Tau fragments generated by Caspase-2, specifically Tau 1-314 and Tau 315-441. In this study, we transiently transfected neuroblastoma cells with plasmids encoding either Tau 1-314 or Tau 315-441 and analyzed changes in cell morphology as well as toxicity using immunofluorescence and confocal microscopy. Furthermore, we aimed to examine the physiological effects of truncated Tau expression on the overall proteome of the transfected neuroblastoma cells through mass spectrometry analysis. Our findings indicate that the Caspase-2-generated truncated Tau fragments exhibit distinct intracellular distributions, leading to the abnormal transport of Tau 315-441 into the nuclear compartment accompanied by the abnormal downregulation of functional and structural nuclear proteins. The generation of Caspase-2-derived truncated Tau fragments may represent an additional mechanism of neuronal toxicity occurring at early stages of the disease, prior to the filamentous aggregation of the Tau protein.