Fig. 4

GVB formation as a protective or degenerative response to proteinopathy? The intracellular aggregation of tau and possibly other proteins elicits GVB formation, a response that may be either a protective or b degenerative. a GVBs could be protective by boosting the lysosomal system, increasing the cells proteolytic capacity or isolating harmful proteins from the cytosol, thereby obviating or reversing ongoing pathological proteinopathy and neurodegeneration. As such, proteinopathy may not proceed to the end-stage in GVB-bearing neurons. b Alternatively, GVBs could signify collapse of the lysosomal system, indicating that the cell is beyond rescue and that proteinopathy will irreversibly progress to the end-stage, kicking-off neurodegeneration. Note that GVBs are not drawn in the degenerating neuron, which is in line with the absence of GVBs from neurons with NFTs. See text for arguments in favor of both hypothetical functional outcomes of GVB formation; blue circles with pink core GVBs; blue lines tau pathology/proteinopathy; dashed neuron neurodegeneration