Immunocytochemistry of neurofibrillary tangles with antibodies to subregions of tau protein: identification of hidden and cleaved tau epitopes and a new phosphorylation site

1992 ◽  
Vol 84 (6) ◽  
Author(s):  
D.W. Dickson ◽  
H. Ksiezak-Reding ◽  
W.-K. Liu ◽  
P. Davies ◽  
A. Crowe ◽  
...  
Keyword(s):  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Protein Identification ◽  
Phosphorylation Site

scholarly journals Association of phosphorylation site of tau protein with neuronal apoptosis in Alzheimer's disease

2003 ◽  
Vol 208 (1-2) ◽  
pp. 17-24 ◽  
Author(s):  
Katsuji Kobayashi ◽  
Hiroyuki Nakano ◽  
Masahiro Hayashi ◽  
Masao Shimazaki ◽  
Yuken Fukutani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neuronal Apoptosis ◽  
Phosphorylation Site

scholarly journals A Protein Kinase, PKN, Accumulates in Alzheimer Neurofibrillary Tangles and Associated Endoplasmic Reticulum-Derived Vesicles and Phosphorylates Tau Protein

1998 ◽  
Vol 18 (18) ◽  
pp. 7402-7410 ◽  
Author(s):  
Toshio Kawamata ◽  
Taizo Taniguchi ◽  
Hideyuki Mukai ◽  
Michinori Kitagawa ◽  
Takeshi Hashimoto ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Alzheimer Neurofibrillary Tangles

scholarly journals The Endogenous and Cell Cycle-dependent Phosphorylation of tau Protein in Living Cells: Implications for Alzheimer’s Disease

1998 ◽  
Vol 9 (6) ◽  
pp. 1495-1512 ◽  
Author(s):  
Susanne Illenberger ◽  
Qingyi Zheng-Fischhöfer ◽  
Ute Preuss ◽  
Karsten Stamer ◽  
Karlheinz Baumann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Cell Cycle ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Chinese Hamster Ovary Cells ◽  
Phosphorylation Site ◽  
Chinese Hamster ◽  
Microtubule Assembly ◽  
Human Neuroblastoma

In Alzheimer’s disease the neuronal microtubule-associated protein tau becomes highly phosphorylated, loses its binding properties, and aggregates into paired helical filaments. There is increasing evidence that the events leading to this hyperphosphorylation are related to mitotic mechanisms. Hence, we have analyzed the physiological phosphorylation of endogenous tau protein in metabolically labeled human neuroblastoma cells and in Chinese hamster ovary cells stably transfected with tau. In nonsynchronized cultures the phosphorylation pattern was remarkably similar in both cell lines, suggesting a similar balance of kinases and phosphatases with respect to tau. Using phosphopeptide mapping and sequencing we identified 17 phosphorylation sites comprising 80–90% of the total phosphate incorporated. Most of these are in SP or TP motifs, except S214 and S262. Since phosphorylation of microtubule-associated proteins increases during mitosis, concomitant with increased microtubule dynamics, we analyzed cells mitotically arrested with nocodazole. This revealed that S214 is a prominent phosphorylation site in metaphase, but not in interphase. Phosphorylation of this residue strongly decreases the tau–microtubule interaction in vitro, suppresses microtubule assembly, and may be a key factor in the observed detachment of tau from microtubules during mitosis. Since S214 is also phosphorylated in Alzheimer’s disease tau, our results support the view that reactivation of the cell cycle machinery is involved in tau hyperphosphorylation.

Intracellular Responses of Glial Cells To Monomeric Tau Protein Are Closely Mediated By Heparan Sulfate Proteoglycans (HSPGs)

2021 ◽  
Author(s):  
Liqing Song ◽  
Daniel E. Oseid ◽  
Evan A. Wells ◽  
Troy Coaston ◽  
Anne S Robinson
Keyword(s):  
Gene Expression ◽  
Heparan Sulfate ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Intracellular Signaling ◽  
Heparan Sulfate Proteoglycans ◽  
C6 Glioma Cells ◽  
Dependent Manner

Abstract The conversion of soluble tau protein to insoluble, hyperphosphorylated neurofibrillary tangles is a major hallmark leading to neuronal death observed in neurodegenerative tauopathies. Recent work suggests that extracellular, soluble tau binds to negatively charged heparan sulfate proteoglycans (HSPGs) available on the cell surface. In addition, LRP1 has recently been recognized as a major tau receptor, mediating tau uptake and spread. We hypothesized based on this data that monomeric tau would be endocytosed in both an HSPG- and LRP-dependent manner, activating intracellular signaling pathways that would regulate cellular phenotypes. Using live-cell confocal microscopy and flow cytometry, we show that soluble 0N4R monomers were rapidly endocytosed by SH-SY5Y and C6 glioma cells, via actin-dependent macropinocytosis. We also demonstrated the crucial role of HSPGs and LRP1 in cellular endocytosis of monomeric tau by observing reduced tau uptake in C6 glial cells with genetic knockouts of xylosyltransferase-1 – a key enzyme in HSPG synthesis – and LRP1. An ERK1/2 inhibition experiment showed that inhibiting the MEK-ERK1/2 signaling pathway attenuated IL-6 and IL-1β gene expression but not TNF-α . An LRP1 knockdown experiment led to an attenuated propensity for tau uptake and further elevated IL-6 gene expression. Collectively, our data suggest that tau has multiple extracellular binding partners that mediate its internalization through distinct mechanisms. Additionally, this study demonstrates the important role of both HSPG and LRP1 in regulating cellular immune responses to tau protein monomer, which provides a novel target for alleviating the neuroinflammatory environment before the formation of neurofibrillary tangles.

Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein

10.1038/78078 ◽  
2000 ◽  
Vol 25 (4) ◽  
pp. 402-405 ◽  
Author(s):  
Jada Lewis ◽  
Eileen McGowan ◽  
Julia Rockwood ◽  
Heather Melrose ◽  
Parimala Nacharaju ◽  
...  
Keyword(s):  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Motor Disturbance
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