Abstract
BackgroundGranulovacuolar degeneration (GVD) is one of the pathological hallmarks of Alzheimer's disease (AD), and it is defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles. Several lines of evidence have suggested that GVDs appear within hippocampal pyramidal neurons in AD when phosphorylated tau begins to aggregate into early-stage neurofibrillary tangles. The aim of this study is to investigate the association of GVDs with phosphorylated tau pathology to determine whether GVDs and phosphorylated tau coexist among different non-AD neurodegenerative disorders.MethodsAn autopsied series of 28 patients with a variety of neurodegenerative disorders and 9 control patients were evaluated. Standard histological stains along with immunohistochemistry using protein markers for GVD and confocal microscopy were utilized.ResultsThe number of neurons with GVDs significantly increased with the level of phosphorylated tau accumulation in the hippocampal regions in non-AD neurodegenerative disorders. At the cellular level, diffuse staining for phosphorylated tau was detected in neurons with GVDs.ConclusionsOur data suggest that GVDs appear in relation to hippocampal phosphorylated tau accumulation in various neurodegenerative disorders, while the presence of phosphorylated tau in GVD-harbouring neurons in non-AD neurodegenerative disorders was indistinguishable from age-related accumulation of phosphorylated tau. Although GVDs in non-AD neurodegenerative disorders have not been studied thoroughly, our results suggest that they are not incidental findings, but rather they appear in relation to phosphorylated tau accumulation, further highlighting the role of GVD in the process of phosphorylated tau accumulation.
Highlights
Granulovacuolar degeneration (GVD) is one of the pathological hallmarks of Alzheimer’s disease (AD) [1] and is defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons [2].Attempts to define the molecular composition of GVDs by immunohistochemical methods led to the identification of a large number of possible protein constituents, suggesting a link between GVD and AD-related neurodegeneration
Immunohistochemical localization of charged multivesicular body protein 2b (CHMP2B) was investigated in the hippocampus of several neurodegenerative disorders, including myotonic dystrophy (MyD), ALS with dementia (ALS-D), Parkinson disease with dementia (PDD), MSA, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and pantothenate kinase-associated neurodegeneration (PKAN) cases
We showed that the number of neurons with CHMP2B-positive GVDs increased in association with phosphorylated tau accumulation in the hippocampus in AD and in a wide range of non-AD neurodegenerative disorders
Summary
Granulovacuolar degeneration (GVD) is one of the pathological hallmarks of Alzheimer’s disease (AD) [1] and is defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons [2].Attempts to define the molecular composition of GVDs by immunohistochemical methods led to the identification of a large number of possible protein constituents, suggesting a link between GVD and AD-related neurodegeneration. Granulovacuolar degeneration (GVD) is one of the pathological hallmarks of Alzheimer’s disease (AD) [1] and is defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons [2]. Intraneuronal dot-like structures morphologically similar to GVDs were labelled by phosphorylation-dependent TAR DNA binding protein (TDP43) antibody [19], in line with the abnormal TDP43 immunoreactivity reported in AD [20,21,22,23,24,25] Both proteasome and endosome pathway dysfunction may be present in GVD-containing cells, as GVD has been detected by antibodies to a cellular marker of proteasome degradation, ubiquitin (Ub) [2,26], to intermediaries in the ubiquitin system, phospho-b-catenin [27] and Pin1 [28], and to the endosome-related protein charged multivesicular body protein 2b (CHMP2B) [29,30]. The aim of this study is to investigate the association of GVDs with phosphorylated tau pathology to determine whether GVDs and phosphorylated tau coexist among different non-AD neurodegenerative disorders
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