Abstract:
:Granulovacuolar degeneration (GVD) is a common feature in Alzheimer's disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC-MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Hondius DC,Koopmans F,Leistner C,Pita-Illobre D,Peferoen-Baert RM,Marbus F,Paliukhovich I,Li KW,Rozemuller AJM,Hoozemans JJM,Smit ABdoi
10.1007/s00401-020-02261-4subject
Has Abstractpub_date
2021-01-25 00:00:00eissn
0001-6322issn
1432-0533pii
10.1007/s00401-020-02261-4pub_type
杂志文章abstract::Thirty-one squirrel monkey fetuses were exposed to lead acetate given to the mothers perorally during the last three-fourths or two-thirds of pregnancy. The mean maternal blood lead concentration of the group was 37 micrograms/100 ml and the individual means ranged from 22-82 micrograms/100 ml. Examination of the cent...
journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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abstract::The pro-inflammatory and blood-brain barrier (BBB) effects of intratumoral (IT) injection of human recombinant tumor necrosis factor-alpha (rTNF-alpha) were studied in the Fischer rat RT-2 glioma model. Animals received a single stereotaxic injection of either 6 x 10(4) U rTNF-alpha or excipient (vehicle) into the cen...
journal_title:Acta neuropathologica
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abstract::A mixed lymphoblastic T cell lymphoma and gonadotroph cell pituitary adenoma occurred 25 years after first resection of the adenoma. Within 1 year the lymphoma overgrew the adenoma, but was still restricted to the sellar region. Histologically, lymphoma and adenoma components were tightly admixed. Possible pathogeneti...
journal_title:Acta neuropathologica
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abstract::An unresolved issue in the study of demyelinating disease is whether blood-brain barrier damage is dependent upon the migration of inflammatory cells into the central nervous system (CNS). In a study of experimental autoimmune encephalomyelitis (EAE) in rabbits, a freeze-dried, paraffin-embedded tissue technique was e...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00692851
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687004
更新日期:1985-01-01 00:00:00
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691896
更新日期:1979-02-15 00:00:00
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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更新日期:1981-01-01 00:00:00
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journal_title:Acta neuropathologica
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更新日期:1976-03-15 00:00:00
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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doi:
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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abstract::An unusual case of cerebellar neurocytoma with rhabdomyomatous differentiation in a 6-year-old boy is reported. Immunocytochemical and ultrastructural features of the tumour were studied. Abortive synapse formation, the presence of clear vesicles and synaptophysin immunoreactivity of the tumour cells indicated its int...
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