Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles

Abstract

Aims-Granulovacuolar degeneration involves the accumulation of large, double membranebound bodies within certain neurons during the course of Alzheimer's disease and other adultonset dementias. Because of the two-layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalled in Alzheimer's disease.Methods-Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for GVD bodies, was evaluated in hippocampal sections prepared from postmortem Braak stage IV and V Alzheimer's disease cases using double-label confocal fluorescence microscopy.Results-GVD bodies colocalized weakly with early-stage autophagy markers LC3 and p62, but strongly with late-stage marker LAMP1 (lysosome-associated membrane protein 1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with CHMP2B (charged multivesicular body protein 2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D.Conclusions-The resultant immunohistochemical signature suggests that GVD bodies contain late-stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. . The data further suggest that failure to complete autolysosome formation may be an important correlate of GVD body accumulation.

Autophagy-Derived Alzheimer’s Pathogenesis

“…GVD bodies are double membrane enclosed partially digested cytoplasmic contents (Okamoto et al, 1991), suggesting an autophagic origin for the GVD. This autophagic association is further confirmed by positive immunostaining for LC3 and p62 (autophagic markers), LAMP1 (lysosome-associated membrane protein 1) and CHMP2B (charged multivesicular body protein 2B) to the GVD bodies (Funk et al, 2011;Yamazaki et al, 2010). These studies suggest that the GVD bodies are enlarged vesicles derived from autophagy and endocytosis.…”

“…Granulovacuolar degeneration (GVD) along with plaques and tangles are the earliest described and also the most prominent histopathologic signs of AD (Anderton, 1997;Ball, 1982;Burger & Vogel, 1973;Funk et al, 2011;Okamoto et al, 1991). Granulovacuolar structures were initially reported for AD in 1911.…”

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

“…CHMP2B is expressed in all neuronal populations and colocalizes with granulovacuolar degenerationone of the pathological hallmarks in AD. 66,67 The partially deleted adjacent gene, POU1F1 (OMIM: 173110), has been reported to cause pituitary hormone deficiency and is associated with mental retardation. 68,69 CHMP2B has also been implicated in endosomal trafficking, the disruption of which could lead to neurodegeneration.…”

Contribution of Multivesicular Bodies to the Prion-Like Propagation of Lesions in Alzheimer’s Disease

“…The truncated protein impairs the fusion of endosome with lysosomes without obvious modification of protein sorting to MVB (Urwin et al, 2010). Staining of tissue from Alzheimer disease patients with CHMP2B showed an accumulation of the protein in vesicular structures resembling GranuloVacuolar Degeneration (Yamazaki et al, 2010;Funk et al, 2011) suggestive of defective autophagic and endocytic pathways in Alzheimer disease. Thus, restoring or enhancing the lysosomal degradation and rates of autophagic protein turnover in a transgenic animal model of amyloid deposition can rescue the phenotype and decrease the amyloid burden (Yang et al, 2011).…”