Neuron‐selective induction of granulovacuolar degeneration bodies: A lysosomal stress response to tau aggregation?

Background Granulovacuolar degeneration bodies (GVBs) are membrane‐bound vacuolar structures harboring a dense core that accumulate in the brains of patients with neurodegenerative disorders, including Alzheimer’s disease and other tauopathies. Insight into the origin of GVBs and their connection to tau pathology has been limited by the lack of suitable experimental models for GVB formation. Method We used confocal, automated, super‐resolution and electron microscopy in different models for seeded tau aggregation. Result We demonstrate that the seeding of tau pathology triggers the formation of GVBs in mouse models in vivo and in primary mouse neurons in vitro . Seed‐induced intracellular tau aggregation, but not seed exposure alone, causes GVB formation in cultured neurons but not astrocytes. The extent of tau pathology strongly correlates with the GVB load. The in vitro tau‐induced GVBs are immunoreactive for the established GVB markers CK1δ, CK1ɛ, CHMP2B, pPERK, peIF2α and pIRE1α. GVBs contain a LAMP1‐ and LIMP2‐positive single membrane that surrounds the dense core and vacuole. The proteolysis reporter DQ‐BSA is detected in the majority of GVBs, demonstrating that GVBs contain degraded endocytic cargo. GFP‐tagged CK1δ accumulates in the GVB core, whereas GFP‐tagged tau or GFP alone do not, indicating selective targeting of cytosolic cargo to GVBs. In addition, GVB positive neurons have increased levels of stress related proteins. Conclusion We established the first in vitro model for GVB formation by seeding tau pathology in primary neurons. The tau‐induced GVBs have the marker signature and morphological characteristics of GVBs in the human brain. We show that GVBs are lysosomal structures that are distinguished by the accumulation of a characteristic subset of proteins in a dense core. Our data indicate that GVB containing neurons are in a state of enhanced cellular stress.