Fig. 2.

Intracellular protein aggregation causes GVB formation. In the human brain, tau pathology and GVBs co-exist on the regional and cellular level. This is explained by a causal relation between tau pathology and GVB development, as intraneuronal tau pathology induces GVB formation in experimental models. Based on the reevaluation of available neuropathological data in the present review, it is conceivable that aggregates of intracellular proteins other than tau – including DPR proteins, α-synuclein and FUS – can similarly instigate GVB formation. In contrast, data from the human brain indicate that extracellular protein aggregation is not sufficient to induce GVB formation. See text for details; blue circles with pink core GVBs; blue lines proteinopathy; ! causal role proven; ? causal role hypothesized