A novel origin for granulovacuolar degeneration in aging and Alzheimer's disease: Parallels to stress granules

The phosphorylated ribosomal protein S6 (pS6) is associated with the 40S ribosomal subunit in eukaryotes and is thought to have a role in RNA storage, degradation, and re-entry into translation. In this study, we found pS6 localized to granulovacuolar degeneration (GVD) within the pyramidal neurons. Immunohistochemical analysis found that nearly 20-fold more neurons contain pS6-positive granules in Alzheimer's disease (AD) hippocampus compared with age-matched controls. Further, pS6-positive granules were more common in neurons not containing neurofibrillary tangles (NFTs), were never associated with extracellular NFTs or in apoptotic neurons, and contained less RNA than neighboring pyramidal neurons not containing pS6-positive granules. In model systems, pS6 is a specific marker for stress granules, and another stress granule protein, p54/Rck, was also found to be a component of GVD in the current study. Stress granules are transient, intracellular, dense aggregations of proteins and RNAs that accumulate as a stress response, protecting cells from apoptosis and inappropriate transcriptional activity, often described as a form of molecular triage. The RNA oxidation modification 8-hydroxyguanosine (8OHG) is strikingly increased in AD, yet this study reports that those neurons with pS6 granules display reduced RNA oxidation demonstrated by lower levels of 8OHG. Since chronic oxidative stress is central to AD pathogenesis, and RNA is a specific oxidative stress target and is intimately associated with stress granule biogenesis in model systems, we suggest that GVD in human brain parallel stress granules, and may in fact be more representative of early disease pathogenesis than traditionally believed. This proposed origin for GVD as a neuroprotective response, may represent a morphologic checkpoint between cell death and reversible cellular stress that proceeds in the absence of other inclusions.