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Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology.

ABSTRACT: 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. Here, we used confocal, automated, super-resolution and electron microscopy to demonstrate that the seeding of tau pathology triggers the formation of GVBs in different mouse models in vivo and in primary mouse neurons in vitro. Seeding-induced intracellular tau aggregation, but not seed exposure alone, causes GVB formation in cultured neurons, but not in astrocytes. The extent of tau pathology strongly correlates with the GVB load. Tau-induced GVBs are immunoreactive for the established GVB markers CK1?, CK1?, CHMP2B, pPERK, peIF2? and pIRE1? and 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 CK1? accumulates in the GVB core, whereas GFP-tagged tau or GFP alone does not, indicating selective targeting of cytosolic proteins to GVBs. Taken together, 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 distinguished by the accumulation of a characteristic subset of proteins in a dense core.

SUBMITTER: Wiersma VI

PROVIDER: S-EPMC6851499 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology.

Wiersma Vera I VI van Ziel Anna Maria AM Vazquez-Sanchez Sonia S Nölle Anna A Berenjeno-Correa Ernesto E Bonaterra-Pastra Anna A Clavaguera Florence F Tolnay Markus M Musters René J P RJP van Weering Jan R T JRT Verhage Matthijs M Hoozemans Jeroen J M JJM Scheper Wiep W

Acta neuropathologica 20190827 6

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. Here, we used confocal, automated, super-resolution and electron microscopy to demonstrate that the seeding of tau p ...[more]

PMID: 31456031

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Project description:BackgroundGranulovacuolar degeneration bodies (GVBs) are intracellular vesicular structures that commonly accompany pathological tau accumulations in neurons of patients with tauopathies. Recently, we developed the first model for GVBs in primary neurons, that requires exogenous tau seeds to elicit tau aggregation. This model allowed the identification of GVBs as proteolytically active lysosomes induced by tau pathology. GVBs selectively accumulate cargo in a dense core, that shows differential and inconsistent immunopositivity for (phosphorylated) tau epitopes. Despite the strong evidence connecting GVBs to tau pathology, these structures have been reported in neurons without apparent pathology in brain tissue of tauopathy patients. Additionally, GVBs and putative GVBs have also been reported in the brain of patients with non-tau proteinopathies. Here, we investigated the connection between pathological protein assemblies and GVBs in more detail.MethodsThis study combined newly developed primary neuron models for tau and α-synuclein pathology with observations in human brain tissue from tauopathy and Parkinson's disease patients. Immunolabeling and imaging techniques were employed for extensive characterisation of pathological proteins and GVBs. Quantitative data were obtained by high-content automated microscopy as well as single-cell analysis of confocal images.ResultsEmploying a novel seed-independent neuronal tau/GVB model, we show that in the context of tauopathy, GVBs are inseparably associated with the presence of cytosolic pathological tau and that intracellular tau aggregation precedes GVB formation, strengthening the causal relationship between pathological accumulation of tau and GVBs. We also report that GVBs are inseparably associated with pathological tau at the single-cell level in the hippocampus of tauopathy patients. Paradoxically, we demonstrate the presence of GVBs in the substantia nigra of Parkinson's disease patients and in a primary neuron model for α-synuclein pathology. GVBs in this newly developed α-synuclein/GVB model are induced in the absence of cytosolic pathological tau accumulations. GVBs in the context of tau or α-synuclein pathology showed similar immunoreactivity for different phosphorylated tau epitopes. The phosphorylated tau immunoreactivity signature of GVBs is therefore independent of the presence of cytosolic tau pathology.ConclusionOur data identify the emergence of GVBs as a more generalised response to cytosolic protein pathology.

Project description:Pathological tau aggregates in Alzheimer's disease (AD) and frontotemporal lobar degeneration-tau (FTLD-tau) adopt distinct conformations differentiated by the AD-tau specific monoclonal antibody (mAb) GT-38 that are not readily visualized using phosphorylation-specific anti-tau mAbs. To determine the extent of co-morbid AD-tau pathology in FTLD-tau, we performed immunohistochemical (IHC) staining with GT-38 and assigned Braak stages of AD-tau in a cohort 180 FTLD-tau cases consisting of corticobasal degeneration (CBD; n = 49), progressive supranuclear palsy (PSP; n = 109), and Pick's disease (PiD; n = 22). Nearly two-thirds of patients (n = 115 of 180, 63.8%) with FTLD-tau had some degree of comorbid AD-tau pathology and 20.5% of the FTLD-tau cohort had Braak stage ≥B2, consistent with medium-to-high-level AD neuropathological change (ADNPC). The PSP group had the highest frequency of medium-high AD-tau pathology compared to other tauopathies (PSP = 31/109, 28.4%; Picks = 2/22, 9.1%, CBD = 4/49, 8.2%) but neuropathological diagnosis was not found to be a significant independent predictor of medium-high AD Braak stage in a multivariate model after accounting for age at death (OR = 1.09; 95% CI = 1.03-1.15; p = 0.002) and CERAD plaque scores (OR = 3.75, 95% CI = 1.58-8.89; p = 0.003), suggesting there is no predilection for a specific FTLD tauopathy to develop AD-tau co-pathology after accounting for age. Patients with FTLD-tau who had, clinically significant, medium-high AD-tau pathology had significantly higher antemortem CSF levels of both total-tau (t-tau; mean = 89.98 pg/ml, SD = 36.70 pg/ml) and phosphorylated-tau (p-tau; mean = 20.45 pg/ml, SD = 9.31 pg/ml) compared to patients with negligible-low AD-tau, t-tau (mean = 43.04 pg/ml, SD = 25.40 pg/ml) and p-tau (mean = 11.90 pg/ml, SD = 4.48 pg/ml) (p ≤ 0.001 both). Finally, in an exploratory analysis in our largest pathology group (PSP) we find an association of GT-38 AD-tau Braak stage with lower baseline MMSE (p = 0.03). Together, these finding validate the use of GT-38 to selectively detect AD-tau pathology in the context of FTLD-tau and provides a novel tool to investigate associations of clinical phenotypes amongst co-morbid tauopathies.

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Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology.

Publications

Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology.

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