Granulovacuolar Degenerations Appear in Relation to Hippocampal Phosphorylated Tau Accumulation in Various Neurodegenerative Disorders

Yamazaki, Yu; Matsubara, Tomoyasu; Takahashi, Tetsuya; Kurashige, Takashi; Dohi, Eisuke; Hiji, Masanori; Nagano, Yoshito; Yamawaki, Takemori; Matsumoto, Masayasu

doi:10.1371/journal.pone.0026996

Cited by 36 publications

(47 citation statements)

References 59 publications

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“…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]. …”

Section: Discussionmentioning

confidence: 87%

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

Lund

Gustafsson

Svensson

et al. 2014

acta neuropathol commun

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BackgroundThe progression of Alzheimer’s disease (AD) is associated with an increase of phosphorylated tau in the brain. One of the earliest phosphorylated sites on tau is Ser262 that is preferentially phosphorylated by microtubule affinity regulating kinase (MARK), of which four isoforms exist. Herein we investigated the expression of MARK1-4 in the hippocampus of non-demented elderly (NDE) and AD cases.ResultsIn situ hybridization revealed a uniform, neuronal distribution of all four isoform mRNAs in NDE and AD. Immunohistochemical analyses using isoform-selective antibodies demonstrated that MARK4 in a phosphorylated form colocalizes with p-tau Ser262 in granulovacuolar degeneration bodies (GVDs) that progressively accumulate in AD. In contrast MARK4 is largely absent in the neuronal cytoplasm. MARK3 was localized to a subset of the GVD-containing neurons and also had a weak general cytoplasmic neuronal staining in both NDE and AD. These results suggest that in AD, phosphorylated MARK3 and MARK4 are sequestered and proteolysed in GVDs. MARK1 and MARK2 were absent in GVDs and exhibited relatively uniform neuronal expressions with no apparent differences between NDE and AD.ConclusionWe found that the phosphorylated and fragmented forms of MARK4 and to some extent MARK3 are present in GVDs in AD, and that this expression is highly correlated with phosphorylation of tau at Ser262. This may represent a cellular defense mechanism to remove activated MARK and p-tau Ser262 from the cytosol, thereby reducing the phosphorylating effect on tau Ser262 that appears to be a critical step for subsequent neurodegeneration.

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Section: Discussionmentioning

confidence: 87%

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

Lund

Gustafsson

Svensson

et al. 2014

acta neuropathol commun

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“…shape of the NFTs, and RTVs themselves would be another substructure of NFTs in addition to PHFs. The number of neurons with GVD bodies increases with the level of accumulation of phosphorylated tau [39], and GVD stage is correlated with the NFT stage [13]. Because the number of GVD bodies is followed by that of RTVs and because NFTs formation is preceded by RTV formation, RTVs may quantitatively connect GVD bodies and NFTs in various tauopathies.…”

Section: Discussionmentioning

confidence: 98%

The identification of raft‐derived tau‐associated vesicles that are incorporated into immature tangles and paired helical filaments

Nishikawa

Nakamori

Hosomi

et al. 2015

Neuropathology Appl Neurobio

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, have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. Methods: We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2-immunopositive material and tau kinases through double immunofluorescence analysis. Results: Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 lm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3b and spleen tyrosine kinase. Conclusions: These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation.

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“…190 The granules are composed of several components including neurofilament proteins (NF), ubiquitin, phosphorylated tau, and other microtubule-associated proteins. 213 Although there have been a few studies of hippocampal GVD in aged animals including rats, wolverines, and dogs, its morphological and immunohistochemical features have not been described in detail. 80,152,219 Neuronal vacuolization was reported in the brain of aged cats, 200 cattle, 52 and horses, 23 however, the correlation of this lesion to aging was not completely confirmed.…”

Section: Neuronal Lesionsmentioning

confidence: 99%

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

et al. 2016

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According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases.

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Granulovacuolar Degenerations Appear in Relation to Hippocampal Phosphorylated Tau Accumulation in Various Neurodegenerative Disorders

Cited by 36 publications

References 59 publications

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

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

The identification of raft‐derived tau‐associated vesicles that are incorporated into immature tangles and paired helical filaments

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

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