Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response

Abstract

Granulovacuolar degeneration (GVD) is characterized by the presence of vacuolar cytoplasmic lesions in nerve cells of the medial temporal lobe. These changes occur in older non-diseased individuals as well as in patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's, sporadic Parkinson's (PD), and Guam diseases. We stained representative paraffin sections from all parts of the brain with anti-pTDP43, anti-CK1d or anti-CK1e from 14 non-demented elderly, 19 AD, 17 non-AD tauopathy, 9 sporadic PD, and 5 TDP43-proteinopathy [amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)] cases. Our results showed five stages of GVD based on its distribution pattern: GVD began in the hippocampal subfields CA1, CA2, and the subiculum. In a second stage, entorhinal cortex, and CA4 neurons exhibited GVD. Additional neurons were involved in the temporal neocortex in stage 3, whereas the affection of the amygdala and/or the hypothalamus marked stage 4. A fifth and final stage was characterized by additional GVD in the cingulate cortex and occasionally in the frontal and parietal cortices as well as in the oral raphe and pedunculopontine tegmental nuclei. The GVD stages correlated with neurofibrillary tangle stages, Consortium to Establish a Registry for AD (CERAD) scores for neuritic plaque pathology, amyloid b-protein deposition phases, cerebral amyloid angiopathy stages, and clinical dementia rating (CDR) scores. No associations were seen between GVD stage and the presence of non-AD tauopathies, PD, ALS, or FTLD cases. In conclusion, GVD affects neurons in a hierarchical sequence that allows the distinction of five stages. The topographic distribution of GVD restricted to regions involved in response to chronic stress could indicate a link between GVD and chronically stressful influences. Moreover, the association of the GVD stages with those of AD-related pathology but not with other neurodegenerative disorders points to a possible role of GVD and the response to chronic stress in the pathogenesis of AD.

MARK4 and MARK3 associate with early tau phosphorylation in Alzheimer’s disease granulovacuolar degeneration bodies

“…Since the granules resembled granulovacuolar degeneration bodies (GVDs) [30, 32], we stained sections in parallel using the GVD-marker CK1δ [28] and counted the number of immunoreactive neurons (Figure 3I). We found a remarkable enhancement in all three markers in AD cases compared to NDE cases in both CA1-CA2 and CA3-CA4.…”

“…MARK3 and MARK4 granules coincided with the presence GVDs (as determined by CK1δ + granules), which are defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles, and that are believed to be part of the autophagic system [22, 32]. Interestingly, it was demonstrated in a recent report that the level of GVDs increases steadily with AD progression, correlating with Braak stage, CERAD score, amyloid beta phase and cognitive state, but does not correlate in other non-AD tauopathies [30]. Another recent study corroborates the view that neurofibrillary and GVD pathologies are tightly associated [35].…”

“…According to the GVD-staging proposed by Thal et al . [30], GVD pathology first appears in CA1-neurons and only in later stages in the entorhinal cortex. The fact that GVD formation is first apparent in CA1-neurons could be due to a higher sensitivity of these neurons to tau phosphorylation, or alternatively a higher ability to engage autophagic GVD processes as a defence mechanism.…”

“…GVDs also stain for cytoskeletal proteins such as neurofilament, tubulin tau and tau kinases [1, 23–28]. GVDs have been shown to be more frequent in AD brains compared to in age-matched controls [29], and a recent study suggests that GVD accumulation is specific to AD, since GVD frequency correlated with every measure of AD severity but was not different in any other non-AD tauopathies compared to control brains [30]. …”

Atypical Alzheimer's disease in an elderly United States resident with amyotrophic lateral sclerosis and pathological tau in spinal motor neurons

“…Spinal cord tau pathology is not exclusively present in MND on geographic isolates (such as Guam) or elsewhere in the world, but has also been reported to occur in AD (34–37). Of note, granulovacuolar degeneration has been shown in a range of neurodegenerative diseases including ALS/PDC on Guam and ALS/AD (38,39). However, the case presented here is also distinct from Guam ALS/PDC because it showed robust cortical Aβ plaque deposits as well as amyloid angiopathy.…”