Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases

Granular/fuzzy astrocytes (GFAs), a subtype of “aging‐related tau astrogliopathy,” are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer’s disease (AD, N = 20) and primary age‐related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90–100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas‐positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.

[1]  E. Huang,et al.  Astrocytic Tau Deposition Is Frequent in Typical and Atypical Alzheimer Disease Presentations. , 2019, Journal of neuropathology and experimental neurology.

[2]  K. Okamoto,et al.  Astrocytic tau pathologies in aged human brain , 2019, Neuropathology : official journal of the Japanese Society of Neuropathology.

[3]  J. Kril,et al.  Chronic traumatic encephalopathy (CTE) is absent from a European community-based aging cohort while cortical aging-related tau astrogliopathy (ARTAG) is highly prevalent , 2019, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[4]  G. Kovacs.  Understanding the Relevance of Aging-Related Tau Astrogliopathy (ARTAG) , 2018, Neuroglia.

[5]  J. Trojanowski,et al.  Connexin‐43 and aquaporin‐4 are markers of ageing‐related tau astrogliopathy (ARTAG)‐related astroglial response , 2018, Neuropathology and applied neurobiology.

[6]  John L. Robinson,et al.  Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain , 2018, Acta Neuropathologica Communications.

[7]  S. Terada,et al.  Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review , 2018, Neuropathology : official journal of the Japanese Society of Neuropathology.

[8]  J. Trojanowski,et al.  Protein astrogliopathies in human neurodegenerative diseases and aging , 2017, Brain pathology.

[9]  John L. Robinson,et al.  Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases , 2017, Journal of neuropathology and experimental neurology.

[10]  D. Dickson,et al.  Distribution and characteristics of transactive response DNA binding protein 43 kDa pathology in progressive supranuclear palsy , 2017, Movement disorders : official journal of the Movement Disorder Society.

[11]  Kortaro Tanaka,et al.  Incipient progressive supranuclear palsy is more common than expected and may comprise clinicopathological subtypes: a forensic autopsy series , 2017, Acta Neuropathologica.

[12]  M. Hasegawa,et al.  The Relationship Between Development of Neuronal and Astrocytic Tau Pathologies in Subcortical Nuclei and Progression of Argyrophilic Grain Disease , 2016, Brain pathology.

[13]  Daniel R. Schonhaut,et al.  PET Imaging of Tau Deposition in the Aging Human Brain , 2016, Neuron.

[14]  C. Brayne,et al.  Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study , 2016, Acta Neuropathologica Communications.

[15]  J. Trojanowski,et al.  Deep clinical and neuropathological phenotyping of Pick disease , 2016, Annals of neurology.

[16]  Jennifer L. Whitwell,et al.  Updated TDP-43 in Alzheimer’s disease staging scheme , 2016, Acta Neuropathologica.

[17]  D. Mann,et al.  Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau , 2015, Acta Neuropathologica.

[18]  Thomas Wisniewski,et al.  Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy , 2015, Acta Neuropathologica.

[19]  Janna H. Neltner,et al.  Primary age-related tauopathy (PART): a common pathology associated with human aging , 2014, Acta Neuropathologica.

[20]  Isidre Ferrer,et al.  Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. , 2014, Journal of neuropathology and experimental neurology.

[21]  John L. Robinson,et al.  Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD) , 2014, Acta Neuropathologica.

[22]  D. Mann,et al.  3R and 4R tau isoforms in paired helical filaments in Alzheimer’s disease , 2013, Acta Neuropathologica.

[23]  Isidro Ferrer,et al.  Globular glial tauopathies (GGT): consensus recommendations , 2013, Acta Neuropathologica.

[24]  D. Mann,et al.  Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain , 2013, Acta Neuropathologica Communications.

[25]  Christine Haberler,et al.  Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series , 2013, Acta Neuropathologica.

[26]  Murray Grossman,et al.  Stages of pTDP‐43 pathology in amyotrophic lateral sclerosis , 2013, Annals of neurology.

[27]  Masato Hasegawa,et al.  Prion-like spreading of pathological α-synuclein in brain , 2013, Brain : a journal of neurology.

[28]  U. Sengupta,et al.  Identification of oligomers at early stages of tau aggregation in Alzheimer's disease , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  O. Yokota,et al.  Pick's disease. , 2012, Advances in experimental medicine and biology.

[30]  J. Trojanowski,et al.  A harmonized classification system for FTLD-TDP pathology , 2011, Acta Neuropathologica.

[31]  Miklós Palkovits,et al.  A peculiar constellation of tau pathology defines a subset of dementia in the elderly , 2011, Acta Neuropathologica.

[32]  Charles Duyckaerts,et al.  National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach , 2011, Acta Neuropathologica.

[33]  H. Kretzschmar,et al.  A new subtype of frontotemporal lobar degeneration with FUS pathology. , 2009, Brain : a journal of neurology.

[34]  D. Munoz,et al.  FUS pathology in basophilic inclusion body disease , 2009, Acta Neuropathologica.

[35]  Isidre Ferrer,et al.  Delineation of Early Changes in Cases with Progressive Supranuclear Palsy‐Like Pathology. Astrocytes in Striatum are Primary Targets of Tau Phosphorylation and GFAP Oxidation , 2009, Brain pathology.

[36]  H. Akiyama,et al.  Clinicopathological characterization of Pick’s disease versus frontotemporal lobar degeneration with ubiquitin/TDP-43-positive inclusions , 2009, Acta Neuropathologica.

[37]  B. Ghetti,et al.  White Matter Tauopathy With Globular Glial Inclusions: A Distinct Sporadic Frontotemporal Lobar Degeneration , 2008, Journal of neuropathology and experimental neurology.

[38]  J. Trojanowski,et al.  Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy , 2007, Neuropathology and applied neurobiology.

[39]  P. Lantos,et al.  Progressive supranuclear palsy (PSP): a quantitative study of the pathological changes in cortical and subcortical regions of eight cases , 2007, Journal of Neural Transmission.

[40]  J. Schneider,et al.  Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration , 2007, Acta Neuropathologica.

[41]  H. Akiyama,et al.  TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2006, Biochemical and biophysical research communications.

[42]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[43]  H. Braak,et al.  Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry , 2006, Acta Neuropathologica.

[44]  Dennis W. Dickson,et al.  Alzheimer Disease With Amygdala Lewy Bodies: A Distinct Form of &agr;-Synucleinopathy , 2006, Journal of neuropathology and experimental neurology.

[45]  S Minoshima,et al.  Diagnosis and management of dementia with Lewy bodies , 2005, Neurology.

[46]  A. Kakita,et al.  Sporadic four-repeat tauopathy with frontotemporal degeneration, parkinsonism and motor neuron disease , 2005, Acta Neuropathologica.

[47]  H. Braak,et al.  The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease‐related pathology , 2005, Neuropathology and applied neurobiology.

[48]  G. Sobue,et al.  Distribution of tuft-shaped astrocytes in the cerebral cortex in progressive supranuclear palsy , 2004, Acta Neuropathologica.

[49]  S. Murayama,et al.  Staging of Argyrophilic Grains: An Age‐Associated Tauopathy , 2004, Journal of neuropathology and experimental neurology.

[50]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[51]  T. Tokuda,et al.  Thorn-shaped astrocytes: possibly secondarily induced tau-positive glial fibrillary tangles , 2004, Acta Neuropathologica.

[52]  J. Holton,et al.  Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule‐binding repeat domains as demonstrated by new specific monoclonal antibodies , 2003, Neuropathology and applied neurobiology.

[53]  Mari Yoshida,et al.  Distribution of astrocytic plaques in the corticobasal degeneration brain and comparison with tuft-shaped astrocytes in the progressive supranuclear palsy brain , 2003, Acta Neuropathologica.

[54]  P. Lantos,et al.  Office of Rare Diseases Neuropathologic Criteria for Corticobasal Degeneration , 2002, Journal of neuropathology and experimental neurology.

[55]  H. Braak,et al.  Phases of Aβ-deposition in the human brain and its relevance for the development of AD , 2002, Neurology.

[56]  Y. Kitamura,et al.  NACP/α-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC) , 2002, Acta Neuropathologica.

[57]  Y. Kitamura,et al.  NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC). , 2002, Acta neuropathologica.

[58]  S. Terada,et al.  An autopsy case of postencephalitic parkinsonism of von Economo type: Some new observations concerning neurofibrillary tangles and astrocytic tangles , 2000, Neuropathology : official journal of the Japanese Society of Neuropathology.

[59]  T. Cooper,et al.  New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1) , 2000, Neurology.

[60]  A. Probst,et al.  Astrocytes expressing hyperphosphorylated tau protein without glial fibrillary tangles in argyrophilic grain disease , 1999, Acta Neuropathologica.

[61]  Tolnay,et al.  Low amyloid (Aβ) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer’s disease , 1999, Neuropathology and applied neurobiology.

[62]  H. Mori.  [Postencephalitic parkinsonism]. , 1999, Ryoikibetsu shokogun shirizu.

[63]  N. Shibata,et al.  Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy , 1998, Acta Neuropathologica.

[64]  A. Monsch,et al.  Apolipoprotein E allele frequencies in argyrophilic grain disease , 1998, Acta Neuropathologica.

[65]  H. Braak,et al.  Argyrophilic grain disease is associated with apolipoprotein E ε2 allele , 1998, Acta Neuropathologica.

[66]  K. Jellinger,et al.  Senile Dementia with Tangles (Tangle Predominant Form of Senile Dementia) , 1998, Brain pathology.

[67]  H. Braak,et al.  Argyrophilic grain disease is associated with apolipoprotein E epsilon 2 allele. , 1998, Acta neuropathologica.

[68]  H. Braak,et al.  Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria , 1998, Journal of Neural Transmission.

[69]  G. Jicha,et al.  Alz‐50 and MC‐1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau , 1997, Journal of neuroscience research.

[70]  Masanori Kato,et al.  Immunohistochemical investigation of tau-positive structures in the cerebral cortex of patients with progressive supranuclear palsy , 1995, Neuroscience Letters.

[71]  D W Dickson,et al.  Widespread cytoskeletal pathology characterizes corticobasal degeneration. , 1995, The American journal of pathology.

[72]  R. Bowser,et al.  FAC1, a novel gene identified with the monoclonal antibody Alz50, is developmentally regulated in human brain. , 1995, Developmental neuroscience.

[73]  I Litvan,et al.  Preliminary NINDS neuropathologic criteria for Steele‐Richardson‐Olszewski syndrome (progressive supranuclear palsy) , 1994, Neurology.

[74]  K. Kosaka.  Diffuse neurofibrillary tangles with calcification: a new presenile dementia. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[75]  H. Iwata,et al.  Non-Alzheimer non-Pick dementia with Fahr's syndrome. , 1992, Clinical neuropathology.

[76]  Masaya Oda,et al.  Glial fibrillary tangles with straight tubules in the brains of patients with progressive supranuclear palsy , 1992, Neuroscience Letters.

[77]  P. Mcgeer,et al.  Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue , 1992, Neuroscience Letters.

[78]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[79]  P. Davies,et al.  A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Peter L. Lantos,et al.  Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome) , 1989, Journal of the Neurological Sciences.

[81]  D. S. Wood,et al.  Criteria for establishing the validity of genetic recombination in myotonic dystrophy , 1989, Neurology.

[82]  H. Braak,et al.  Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult onset dementia without Alzheimer changes , 1987, Neuroscience Letters.