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a(HBP:"Tau aggregates")

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Components

Entity

Name
Tau aggregates
Namespace
HBP
Namespace Version
20181128
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/7e4be528f12abd28be768b62402fba6e083eaf9e/export/hbp-names.belns

Appears in Networks 33

M1 muscarinic acetylcholine receptor in Alzheimer’s disease v1.0.0

This file encodes the article M1 muscarinic acetylcholine receptor in Alzheimer’s disease by Jiang et al, 2014

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment v1.0.1

Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease v1.0.0

Analysis of Isoform-specific Tau Aggregates Suggests a Common Toxic Mechanism Involving Similar Pathological Conformations and Axonal Transport Inhibition v1.0.1

Adenosine A1 receptor antagonist 64627 alleviates axonopathy caused by human Tau ΔK280 v1.0.0

Identification of the Tau phosphorylation pattern that drives its aggregation v1.0.0

Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways v1.0.1

Anti-aggregant tau mutant promotes neurogenesis v1.0.0

Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. v1.0.0

Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies v1.0.0

Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro v1.0.0

This file encodes the article Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro by Nobuhara et. al. 2017

Tau oligomers-Cytotoxicity, propagation, and mitochondrial damage v1.0.0

Tau oligomers-Cytotoxicity, propagation, and mitochondrial damage from Shafiei et al., 2017

Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies v1.0.0

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies v1.0.0

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport. v1.0.0

Tau oligomers and tau toxicity in neurodegenerative disease v1.0.0

Tau oligomers and tau toxicity in neurodegenerative disease by Ward et al., 2012

Clearance of Amyloid Beta and Tau in Alzheimer’s Disease:from Mechanisms to Therapy v1.0.1

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo v1.0.0

Alzheimer’s disease and the autophagic-lysosomal system v1.0.0

The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease v1.0.0

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.0

Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity v1.0.0

Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability v1.0.0

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation v1.0.0

Inert and seed-competent tau monomers suggest structural origins of aggregation v1.0.0

Screening of a neuronal cell model of Tau pathology for therapeutic compounds v1.0.0

Caenorhabditis elegans models of tauopathy v1.0.0

Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes v1.0.0

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase. v1.0.0

Tau in physiology and pathology v1.0.0

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders v1.0.0

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.1

In-Edges 224

a(CHEBI:nicotine) increases a(HBP:"Tau aggregates") View Subject | View Object

The long-term nicotine treatment caused faster tau aggregation in CA1 pyramidal neurons PubMed:25514383

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
Pyramidal Cells
MeSH
Alzheimer Disease

a(CHEBI:nicotine) increases a(HBP:"Tau aggregates") View Subject | View Object

The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase PubMed:25514383

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:"p38MAPK cascade") increases a(HBP:"Tau aggregates") View Subject | View Object

The possible mechanism by which nicotine enhances the aggregation of tau is through the activation of p38-MAP kinase PubMed:25514383

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(FPLX:HSP90) regulates a(HBP:"Tau aggregates") View Subject | View Object

However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017). PubMed:29311797

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a(CHEBI:Thrombin) increases a(HBP:"Tau aggregates") View Subject | View Object

Thrombin may also be influencing tau pathology, as treatment of immortalized hippocampal neuronal cells (HT22 cells) with thrombin resulted in the formation of thioflavin-S positive tau aggregates within 24 h, followed by an increase in cell death at 72 h (37). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Hippocampus
Text Location
Review

bp(MESH:Autophagy) decreases a(HBP:"Tau aggregates") View Subject | View Object

Stimulating autophagy either through serum withdrawal or rapamycin treatment in SH-SY5Y cells overexpressing P301L tau that had been induced to aggregate led to substantial reduction in aggregates that was prevented by 3-MA (70). PubMed:24027553

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Text Location
Review

a(MESH:Autophagosomes) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Electron microscopic analysis of brain tissue from confirmed AD cases revealed that AVs accumulated in dystrophic neurites and correlated with the presence of filamentous tau (79). However, this correlation was not quantified (79).Similar results were observed in mouse models of AD. PubMed:24027553

Appears in Networks:
Annotations
MeSH
Alzheimer Disease
Text Location
Review

a(MESH:Trehalose) decreases a(HBP:"Tau aggregates") View Subject | View Object

In a cell line expressing the repeat domain of tau containing the FTDP-17ΔK280 mutant, treatment with the disaccharide trehalose, an mTor-independent autophagy activator, significantly reduced aggregated tau as measured by Thioflavin-S staining, as well as total tau levels both soluble and insoluble as detected by western blotting (96). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Frontotemporal Dementia
Text Location
Review

bp(MESH:Autophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

This is supported by evidence that full-length tau, which has a lower propensity for aggregating, is cleared by the proteasome while caspase- cleaved tau, which is more aggregate prone, goes through autophagy (72). Also, aggregated tau can be cleared by inducing autophagy (70, 96). PubMed:24027553

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Text Location
Review

bp(MESH:Autophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Soluble, monomeric tau is an ideal proteasomal substrate. Indeed, it has been clearly demonstrated that tau can be degraded by the proteasome (65–67, 73). It thus can be suggested that under physiologic circumstances much of tau is degraded in this manner, with select modified forms being cleared by autophagy.However, within the context of the AD milieu, additional tau modifications and degradative impairments may cause the balance to shift away from proteasomal degradation toward autophagy. PubMed:24027553

Appears in Networks:
Annotations
MeSH
Alzheimer Disease
Text Location
Review

bp(MESH:Autophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

For example, as discussed above, certain modified forms of tau, such as caspase-cleaved tau, have a stronger tendency to aggregate. As tau begins to assemble into oligomers, it may become increasingly undesirable as a proteasomal substrate. These low-order, soluble oligomers may be preferentially degraded by autophagy. PubMed:24027553

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Text Location
Review

act(p(HGNCGENEFAMILY:Proteasome)) causesNoChange deg(a(HBP:"Tau aggregates")) View Subject | View Object

Soluble, monomeric tau is an ideal proteasomal substrate. Indeed, it has been clearly demonstrated that tau can be degraded by the proteasome (65–67, 73). It thus can be suggested that under physiologic circumstances much of tau is degraded in this manner, with select modified forms being cleared by autophagy.However, within the context of the AD milieu, additional tau modifications and degradative impairments may cause the balance to shift away from proteasomal degradation toward autophagy. PubMed:24027553

Appears in Networks:
Annotations
MeSH
Alzheimer Disease
Text Location
Review

p(HBP:"Tau C3") increases a(HBP:"Tau aggregates") View Subject | View Object

For example, as discussed above, certain modified forms of tau, such as caspase-cleaved tau, have a stronger tendency to aggregate. As tau begins to assemble into oligomers, it may become increasingly undesirable as a proteasomal substrate. These low-order, soluble oligomers may be preferentially degraded by autophagy. PubMed:24027553

Appears in Networks:
Annotations
Text Location
Review

p(HBP:"Tau C3") increases a(HBP:"Tau aggregates") View Subject | View Object

Caspase cleavage of tau may play a role in stimulating the tau aggregation seen in AD. Indeed, in vitro polymerization assays demonstrate that caspase-cleaved tau has a greater propensity to aggregate compared to full-length tau (23, 55). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Alzheimer Disease
Text Location
Review

act(p(HGNC:HTRA1)) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Tubulin was later identified as a substrate for HTRA1, suggesting HTRA1 may be involved in mediating microtubule function (42, 43). A more recent study showed that HTRA1 can cleave recombinant tau in vitro into multiple fragments of varying sizes, and furthermore can degrade insoluble and fibrillarized tau (16). PubMed:24027553

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Text Location
Review

deg(p(HGNC:MAPT, frag("561_685"))) increases a(HBP:"Tau aggregates") View Subject | View Object

Thrombin cleavage of the repeat domain construct yielded fragments that rapidly aggregated, which closely correlated with toxicity in cell culture (15). These fragments can also induce the aggregation of full-length tau (39). PubMed:24027553

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Text Location
Review

p(HGNC:DCTN4) decreases a(HBP:"Tau aggregates") View Subject | View Object

Moreover, constitutive inactivation of p62 in mice resulted in aggregated tau proteins with Lys63–Ub chains (Babu et al., 2008). PubMed:23528736

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p(HGNC:MAPT, frag("561_685")) increases a(HBP:"Tau aggregates") View Subject | View Object

Overexpressing only the repeat domain of tau containing an FTDP-17 mutation in neuroblastoma cells leads to tau aggregation as well as the appearance of smaller proteolytic fragments. Using the autophagy inhibitor 3-methyladenine (3-MA) to block the formation of autophagosomes led to an increase in both soluble and insoluble tau (94). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Frontotemporal Dementia
Text Location
Review

act(p(HGNCGENEFAMILY:Caspases)) increases a(HBP:"Tau aggregates") View Subject | View Object

In both studies caspase activation correlated with the appearance and increase over time of caspase-cleaved tau species, which appeared to subsequently form aggregates in the neurons (63). While the mechanism is unclear, a possibility is that accumulating proteins might be a factor in initiating caspase activation. PubMed:24027553

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Text Location
Review

path(HBP:neurotoxicity) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Thrombin cleavage of the repeat domain construct yielded fragments that rapidly aggregated, which closely correlated with toxicity in cell culture (15). These fragments can also induce the aggregation of full-length tau (39). PubMed:24027553

Appears in Networks:
Annotations
Text Location
Review

a(MESH:"BSc 3094") decreases a(HBP:"Tau aggregates") View Subject | View Object

In line with these observations, the presynaptic impairment in proaggregant Tau transgenic slices can be reversed by 64627 or BSc3094 without causing adverse effects in controls (Fig. 4F and Fig. S6) PubMed:27671637

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a(HBP:"Tau Protein Secondary Structure, Turn") decreases a(HBP:"Tau aggregates") View Subject | View Object

Our finding that the resulting Tau species with phosphorylation at Ser202/Th205, but with a disrupted turn-like structure, forms abundant fibers detectable by thioflavin fluorescence or electron microscopy (Figs. 2 and 4) suggests the initial turn-like structure induced by the phosphorylation of only Ser202 and Thr205 is protective against aggregation. PubMed:28784767

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a(HBP:"Tau Protein Secondary Structure, Turn") decreases a(HBP:"Tau aggregates") View Subject | View Object

Indeed, Tau phosphorylation at the three positions, Ser202/Thr205/Ser208, while not at Ser262, is sufficient to induce aggregation without the addition of any exogenous aggregation inducer. PubMed:28784767

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p(HBP:"Tau epitope, AT8") increases a(HBP:"Tau aggregates") View Subject | View Object

Indeed, Tau phosphorylation at the three positions, Ser202/Thr205/Ser208, while not at Ser262, is sufficient to induce aggregation without the addition of any exogenous aggregation inducer. PubMed:28784767

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p(HGNC:MAPT, var("pGly207Val")) increases a(HBP:"Tau aggregates") View Subject | View Object

When combined with ERK2 catalyzed phosphorylation, the turn-like disrupting G207V mutation in TauF8 hence leads to fast aggregation that already occurs during the phosphorylation reaction. PubMed:28784767

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a(CHEBI:"cytochalasin D") causesNoChange tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

In contrast, disruption of actin polymerization with Cytochalasin D had little effect on the entry of aggregated tau (total fluorescent intensity and number of objects; Figures 5D–5F; Figure S5) PubMed:29590627

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a(CHEBI:"cytochalasin D") causesNoChange tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Conversely, dynamin inhibition significantly reduced the entry of aggregated tau, with no significant effects of Cytochalasin D (Figure S6) at this relatively high molar concent of aggregated tau PubMed:29590627

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a(CHEBI:dynasore) decreases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

The effect of dynamin inhibition on the entry of aggregated tau was more pronounced than on monomeric tau (Figures 4D–4F). The total fluorescent intensity of intracellular aggregated taupHrodo was consistently reduced by more than 70% at 1 and 3 hr after tau addition (Figure 4E), and the number of taupHrodo- positive objects was reduced by 95% (Figure 4F) PubMed:29590627

Appears in Networks:

a(CHEBI:dynasore) decreases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Conversely, dynamin inhibition significantly reduced the entry of aggregated tau, with no significant effects of Cytochalasin D (Figure S6) at this relatively high molar concent of aggregated tau PubMed:29590627

Appears in Networks:

a(CHEBI:heparin) causesNoChange tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

We confirmed that heparin within the aggregated tau preparations did not contribute to tau entry into neurons, finding that uptake of both monomeric and aggregated tau was unaffected in the presence of heparin (Figures S4C and S4D PubMed:29590627

Appears in Networks:

a(GO:"early endosome") association a(HBP:"Tau aggregates") View Subject | View Object

As early as 1 hr after the addition of extracellular tau, monomeric and aggregated tau-Dylight were co-localized in EEA1+ early endosomes PubMed:29590627

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a(GO:"late endosome") association a(HBP:"Tau aggregates") View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

a(GO:lysosome) association a(HBP:"Tau aggregates") View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

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a(GO:lysosome) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Thus, monomeric and aggregated tau both efficiently enter neurons via the endosome/lysosome system, and they are actively trafficked within vesicles over long distances within neurons over several hours PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After extensive washing, monomeric and aggregated tau-Dylight were both detected within cells expressing the neuron-specific microtubule-associated protein MAP2, confirming that both forms of tau enter neurons PubMed:29590627

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a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Tau-Dylight was found predominantly within the somatic compartment of neurons (Figure 1A) PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After a 4-hr incubation with extracellular tau, flow cytometry analysis (Figures 1B and 1C) revealed that 83% and 73% of dissociated cells contained monomeric or aggregated tau-Dylight, respectively, demonstrating that extracellular tau efficiently enters human neurons in culture PubMed:29590627

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a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Internalization of aggregated tau-pHrodo (Figure 2D) was also found to be concentration dependent (Figure 2E) PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

These kinetics of aggregated tau-pHrodo entry are similar to that of both lower concentrations of monomeric tau (2.5 nM) and of low-molecular weight (10-kDa) dextran-pHrodo (same molarity as monomeric tau samples; Figures S5A–S5C PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

bp(GO:endocytosis) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Thus, monomeric and aggregated tau both efficiently enter neurons via the endosome/lysosome system, and they are actively trafficked within vesicles over long distances within neurons over several hours PubMed:29590627

Appears in Networks:

bp(GO:endocytosis) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

These data indicate that, at the concentrations studied, aggregated tau enters neurons almost entirely via endocytosis PubMed:29590627

Appears in Networks:

act(p(HGNC:DNM1)) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

The effect of dynamin inhibition on the entry of aggregated tau was more pronounced than on monomeric tau (Figures 4D–4F). The total fluorescent intensity of intracellular aggregated taupHrodo was consistently reduced by more than 70% at 1 and 3 hr after tau addition (Figure 4E), and the number of taupHrodo- positive objects was reduced by 95% (Figure 4F) PubMed:29590627

Appears in Networks:

act(p(HGNC:DNM1)) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Conversely, dynamin inhibition significantly reduced the entry of aggregated tau, with no significant effects of Cytochalasin D (Figure S6) at this relatively high molar concent of aggregated tau PubMed:29590627

Appears in Networks:

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) increases a(HBP:"Tau aggregates") View Subject | View Object

This may be due to the strong Tau pathology of the toxic pro-aggregant TauRDΔK leading to Tau aggregation, loss of synapses and loss of neurons PubMed:29202785

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a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:"Tau aggregates") View Subject | View Object

Trehalose, an natural disaccharide and mTOR-independent activator of autophagy (Sarkar et al., 2007), showed an effect on neuronal survival, reducing the level of tau aggregates in the brain of human tauopathy model mice (Kruger et al., 2011; Rodriguez-Navarro et al., 2010; Schaeffer et al., 2012). PubMed:23528736

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:"methylene blue") decreases a(HBP:"Tau aggregates") View Subject | View Object

Methylene blue, which has been known to directly inhibit tau aggregation, is also capable to induce autophagy and reduce total and phospho-tau levels with improved cognitive performance in tau transgenic mice by oral administration (Congdon et al., 2012). PubMed:23528736

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bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association a(HBP:"Tau aggregates") View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"Phenylthiazolyl-hydrazide") decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

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a(CHEBI:anthraquinone) decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

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a(CHEBI:benzothiazoles) decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

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a(CHEBI:phenothiazines) decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

Appears in Networks:

a(CHEBI:polyphenol) decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

Appears in Networks:

a(CHEBI:rhodanine) decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

Appears in Networks:

a(PUBCHEM:53789478) decreases a(HBP:"Tau aggregates") View Subject | View Object

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41] PubMed:21882945

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(HBP:"Tau aggregates") View Subject | View Object

However, hyperphosphorylated forms of tau are more prone to aggregate, which might decrease their solubility and remove them from normal cycling PubMed:21882945

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p(HGNC:MAPT, var("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

However, under potentially proteotoxic conditions, the post-translational modifications or mutations that damage tau’s affinity for microtubules and favor its aggregation are thought to generate a molecular ‘danger signal’ that specifically alerts the quality control system [112,113]. PubMed:21882945

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tloc(p(MGI:Mapt), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) increases a(HBP:"Tau aggregates") View Subject | View Object

Confocal FRET image analysis showed robust tau aggregation in primary neurons treated with control IgG-immunodepleted rTg4510 brain extracts (Figure 2, B and C).The 6C5 antibody most successfully reduced tau uptake by immunodepletion (>90% reduction), and Tau13 and HT7 showed intermediate effects (approximately 60% reductions) (Figure 2, B and C) PubMed:28408124

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Tauopathies
Text Location
Results

a(CHEBI:dextran) association a(HBP:"Tau aggregates") View Subject | View Object

Evidence shows that tau aggregates colocalize with dextran and HeLa cells, hinting that internalized aggregates are transported in endosomal vesicles and passed through the endosomal pathway to lysosomes (Wu et al., 2013) PubMed:28420982

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Exosomes
MeSH
Alzheimer Disease

bp(GO:endocytosis) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:endosome), toLoc(GO:lysosome)) View Subject | View Object

Evidence shows that tau aggregates colocalize with dextran and HeLa cells, hinting that internalized aggregates are transported in endosomal vesicles and passed through the endosomal pathway to lysosomes (Wu et al., 2013) PubMed:28420982

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Exosomes
MeSH
Alzheimer Disease

bp(MESH:"Neuronal Plasticity") association a(HBP:"Tau aggregates") View Subject | View Object

A recent study showed that neuronal networks facilitate cell-to-cell transfer of tau via synapses; using a microfluidic device they demonstrated that decreasing synaptic connections weakens tau transfer and the subsequent aggregation on the acceptor cell (Calafate et al., 2015) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Low
MeSH
Entorhinal Cortex

complex(a(GO:"cell surface"), a(HBP:"Tau aggregates")) hasComponent a(HBP:"Tau aggregates") View Subject | View Object

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complex(a(HBP:"Tau aggregates"), a(MESH:"Heparan Sulfate Proteoglycans")) hasComponent a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

complex(a(HBP:"Tau aggregates"), a(MESH:"Heparan Sulfate Proteoglycans")) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular space"), toLoc(GO:"intracellular part")) View Subject | View Object

Previous studies suggest that uptake of aggregated tau from the extracellular space depends on interaction with heparan sulfate proteoglycans (HSPGs; Holmes and Diamond, 2014) PubMed:28420982

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Exosomes
MeSH
Alzheimer Disease

complex(a(HBP:"Tau aggregates"), a(MESH:"Heparan Sulfate Proteoglycans")) increases a(HBP:"Tau aggregates") View Subject | View Object

Basically, pathogenic tau aggregates use HSPGs to bind the cell surface of a neuron. This actively stimulates macropinocytosis, leading to propagation of aggregates between cells in culture and aggregate uptake in vivo (Holmes et al., 2013) PubMed:28420982

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

sec(p(HGNC:MAPT)) association a(HBP:"Tau aggregates") View Subject | View Object

Significantly, evidence suggests that tau secretion is partly mediated by ectosomal vesicles and that pathological tau accumulation in cells leads to a deviation toward tau secretion by exosomal vesicles (Dujardin et al., 2014a) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Exosomes
MeSH
Alzheimer Disease

bp(GO:"glucocorticoid receptor signaling pathway") association a(HBP:"Tau aggregates") View Subject | View Object

In addition, XAP2 coordinates with Hsp90 to regulate glucocorticoid receptor signaling (Laenger et al., 2009), which has also been implicated in the production of pathogenic tau (Pinheiro et al., 2016). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:FKBP4) increases a(HBP:"Tau aggregates") View Subject | View Object

FKBP52 interacts both physically and functionally with tau and promotes tau aggregation in vitro (Giustiniani et al., 2015; Meduri et al., 2016). PubMed:29311797

Appears in Networks:

complex(p(FPLX:HSP90), p(HGNC:FKBP5)) increases a(HBP:"Tau aggregates") View Subject | View Object

Contrary to the neuroprotective effects of CyP40, two FK506- binding proteins (FKBPs) have been shown to stimulate toxic tau aggregation (Blair et al., 2013; Giustiniani et al., 2015; Kamah et al., 2016). One of these, FKBP51, coordinates with Hsp90 to preserve toxic tau oligomers in vivo (Blair et al., 2013). PubMed:29311797

Appears in Networks:

p(HGNC:PPID) decreases a(HBP:"Tau aggregates") View Subject | View Object

CyP40 was recently shown to disaggregate tau fibrils in vitro and prevents toxic tau accumulation in vivo preserving memory, demonstrating a neuroprotective role for CyP40 in the brain (Baker et al., 2017). PubMed:29311797

Appears in Networks:

p(HGNC:AHSA1) increases a(HBP:"Tau aggregates") View Subject | View Object

Since Aha1 levels are repressed in aging, but are abnormally preserved in AD, tau aggregation could be accelerated in part by Aha1 in the AD brain. PubMed:29311797

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:HDAC6) association a(HBP:"Tau aggregates") View Subject | View Object

While a direct role of XAP2 in tau pathogenesis has not been described, studies have shown that XAP2 is activated by histone deacetylase (HDAC) 6, which has been linked to pathogenic tau (Kekatpure et al., 2009; Cook et al., 2012; Selenica et al., 2014). PubMed:29311797

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MeSH
Cerebral Cortex

a(CL:0000129) increases tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) View Subject | View Object

In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin-dependent (reviewed in [169]). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis [170]. As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. Three plausible mechanisms of tau spreading are shown schematically in Figure 6. Additionally, it appea rs that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171]. PubMed:26751493

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) View Subject | View Object

The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167]. PubMed:26751493

Appears in Networks:

tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167]. PubMed:26751493

Appears in Networks:

bp(GO:"cell-cell signaling via exosome") isA tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) View Subject | View Object

Appears in Networks:

bp(GO:"clathrin-dependent endocytosis") isA tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) View Subject | View Object

Appears in Networks:

bp(GO:macropinocytosis) isA tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) View Subject | View Object

Appears in Networks:

composite(a(HBP:"Tau aggregates"), p(HGNC:MAPT)) hasComponent a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) increases a(HBP:"Tau aggregates") View Subject | View Object

However, the rate of polymerization (kapparent) did not differ between hT40 tau and S422E tau. At 360 min, a similar intensity of light scattering was observed for hT40 (122.5 ± 1.2) and S422E tau (134.5±1.7) indicating that the extent of aggregate formation was comparable between these two proteins. ThS fluorescence, measured at 360min, alsowas comparable between hT40 aggregates (946.4 ± 73.8) and S422E aggregates (927.9 ± 63.7). PubMed:27373205

Appears in Networks:

composite(a(HBP:"Tau aggregates"), p(HGNC:MAPT, var("p.S422E"))) hasComponent a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.S422E")) increases a(HBP:"Tau aggregates") View Subject | View Object

However, the rate of polymerization (kapparent) did not differ between hT40 tau and S422E tau. At 360 min, a similar intensity of light scattering was observed for hT40 (122.5 ± 1.2) and S422E tau (134.5±1.7) indicating that the extent of aggregate formation was comparable between these two proteins. ThS fluorescence, measured at 360min, alsowas comparable between hT40 aggregates (946.4 ± 73.8) and S422E aggregates (927.9 ± 63.7). PubMed:27373205

Appears in Networks:

a(CHEBI:"arachidonic acid") increases a(HBP:"Tau aggregates") View Subject | View Object

Employing recombinant full-length hT40, we observe the presence of oligomers approximately 15 min after the addition of the anionic inducer arachidonic acid, whereas filament formation requires 5–6 h to attain steady state (Figures 1A–1C) PubMed:22817713

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Annotations
Confidence
High
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

Appears in Networks:

a(HBP:"Tau oligomers") increases a(HBP:"Tau aggregates") View Subject | View Object

Time-course aggregation analysis revealed that dimerization precedes tau oligomerization which, in turn, is an earlier event than the formation of full-length filaments PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:HSPA1A) decreases a(HBP:"Tau aggregates") View Subject | View Object

Previous findings indicate that Hsp70 prevents tau toxicity by preserving tau in its soluble form and preventing it from aggregating by binding to exposed hydrophobic residues [33] PubMed:22817713

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Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:HSPA1A) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

It has also been demonstrated that Hsp70 can facilitate the degradation of pre-formed aggregates [33] PubMed:22817713

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Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

The tau protein becomes highly phosphorylated in AD and this is likely to induce a conformational change causing its detachment from microtubules and its accumulation in aggregates [3] PubMed:22817713

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Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Ser, 202)) association a(HBP:"Tau aggregates") View Subject | View Object

TNT1 also co-localizes in tissue with the phospho-epitope defined by the AT8 antibody, indicating that PAD exposure represents an early event in AD pathology PubMed:22817713

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Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Thr, 205)) association a(HBP:"Tau aggregates") View Subject | View Object

TNT1 also co-localizes in tissue with the phospho-epitope defined by the AT8 antibody, indicating that PAD exposure represents an early event in AD pathology PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

bp(GO:"lysosomal microautophagy") decreases a(HBP:"Tau aggregates") View Subject | View Object

On the one hand, it is beneficial to the clearance of tau aggregates PubMed:29626319

Appears in Networks:

a(CHEBI:rolipram) decreases a(HBP:"Tau aggregates") View Subject | View Object

Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin PubMed:26692334

Appears in Networks:

act(complex(GO:"proteasome complex")) decreases a(HBP:"Tau aggregates") View Subject | View Object

We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. PubMed:26041011

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 280)) increases a(HBP:"Tau aggregates") View Subject | View Object

Surprisingly, we show that tau acetylation alters phosphorylation at residues S202/T205 (comprising the AT8 epitope), indicating acetylation-dephosphorylation cross-talk. Using a series of biochemical approaches, we found that K280/K281 acetylation impaired tau-mediated MT assembly function and also significantly enhanced tau aggregation. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds PubMed:28287136

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 281)) increases a(HBP:"Tau aggregates") View Subject | View Object

Surprisingly, we show that tau acetylation alters phosphorylation at residues S202/T205 (comprising the AT8 epitope), indicating acetylation-dephosphorylation cross-talk. Using a series of biochemical approaches, we found that K280/K281 acetylation impaired tau-mediated MT assembly function and also significantly enhanced tau aggregation. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds PubMed:28287136

Appears in Networks:

p(HBP:"cis p-tau") increases a(HBP:"Tau aggregates") View Subject | View Object

Pin1 accelerates cis to trans conversion to prevent accumulation of pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. PubMed:23157676

Appears in Networks:

p(HBP:"tubulin-binding repeat 3") increases a(HBP:"Tau aggregates") View Subject | View Object

We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states. PubMed:23832849

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) decreases a(HBP:"Tau aggregates") View Subject | View Object

This indicates that O-GlcNAcylation prevents the aggregation of tau in a manner that does not affect its normal phosphorylation state. PubMed:22833681

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys)) decreases a(HBP:"Tau aggregates") View Subject | View Object

These data indicate that Lys methylation depressed the intrinsic aggregation propensity of tau, and did so in part by increasing the concentration of tau needed to support fibril formation. PubMed:24869773

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 231)) increases a(HBP:"Tau aggregates") View Subject | View Object

Pin1 binds to phosphorylated Thr231 of tau and facilitates the dephosphorylation of phosphoThr231 through isomerization (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999a). Phosphorylation at Thr231 on tau is associated with the early events of tau aggregation and NFT (Augustinack et al., 2002). Pin1 binds and isomerizes the proline imidic peptide bond following the phosphothreonine 231 PubMed:22926167

Appears in Networks:

p(HGNC:MAPT, var("p.Lys280Gln")) increases a(HBP:"Tau aggregates") View Subject | View Object

Thus, K → Q substitutions within the critical PHF6* motif, in the apparent absence of other tau PTMs, appears sufficient to accelerate tau aggregation in vitro. PubMed:28287136

Appears in Networks:

p(MGI:Crhr1) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). PubMed:25125464

Appears in Networks:
Annotations
Uberon
hippocampal formation

complex(p(HGNC:MAPT), p(HGNC:OTUB1)) increases a(HBP:"Tau aggregates") View Subject | View Object

Since Otub1 interacts with Tau and promotes phosphorylated and aggregated Tau levels in primary neurons, we hypothesized that Otub1 could act as a Tau deubiquitinase, interfering with pathological Tau degradation and hence Tau aggregation. PubMed:28083634

Appears in Networks:

p(HGNC:OTUB1) increases a(HBP:"Tau aggregates") View Subject | View Object

Expression of the candidate deubiquitinases Otub1, USP5, and USP9x in this assay demonstrated significantly increased Tau aggregation following expression of Otub1 (Fig. 2a; Fig. S3), not observed following expression of USP5 or USP9x (Fig. S3). PubMed:28083634

Appears in Networks:

p(HGNC:OTUB1) increases a(HBP:"Tau aggregates") View Subject | View Object

Endogenous Otub1 depletion significantly inhibited Tau aggregation, with the level of inhibition correlating with the level of knockdown efficiency,while use of a control siRNA did not affect levels of Otub1 nor aggregation efficiency (Fig. 2b). PubMed:28083634

Appears in Networks:

p(HGNC:OTUB1) increases a(HBP:"Tau aggregates") View Subject | View Object

Taken together, our data indicate that Otub1, a deubiquitinating enzyme, is a novel positive regulator of Tau aggregation and Tau stability in vitro, in a nonneuronal cell line. PubMed:28083634

Appears in Networks:

p(HGNC:OTUB1) increases a(HBP:"Tau aggregates") View Subject | View Object

Otub1 expression strikingly enhanced detergent-resistant AT8-positive Tau accumulation compared with GFP-infected neurons (Fig. 4b), indicating that Otub1 increased Tau-seeded Tau aggregation in primary neurons, corroborating the results obtained in a nonneuronal cell line. PubMed:28083634

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MeSH
Neurons

p(HGNC:OTUB1) negativeCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Interestingly, Otub1 expression is gradually downregulated with increasing Tau-seeded Tau aggregation (Fig. S4a), which could be considered as a protective mechanism. PubMed:28083634

Appears in Networks:
Annotations
MeSH
Hippocampus

p(HGNC:USP5) causesNoChange a(HBP:"Tau aggregates") View Subject | View Object

Expression of the candidate deubiquitinases Otub1, USP5, and USP9x in this assay demonstrated significantly increased Tau aggregation following expression of Otub1 (Fig. 2a; Fig. S3), not observed following expression of USP5 or USP9x (Fig. S3). PubMed:28083634

Appears in Networks:

p(HGNC:USP9X) causesNoChange a(HBP:"Tau aggregates") View Subject | View Object

Expression of the candidate deubiquitinases Otub1, USP5, and USP9x in this assay demonstrated significantly increased Tau aggregation following expression of Otub1 (Fig. 2a; Fig. S3), not observed following expression of USP5 or USP9x (Fig. S3). PubMed:28083634

Appears in Networks:

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association a(HBP:"Tau aggregates") View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

Appears in Networks:

bp(GO:autophagy) association a(HBP:"Tau aggregates") View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Wang et al., using an N2a neuroblastoma cell line that expresses the repeat domain of tau with an FTD-17 mutation (TauRDΔK280), has demonstrated that tau aggregates can be degraded by macroautophagy [48] PubMed:29758300

Appears in Networks:

tloc(complex(GO:"SNARE complex"), fromLoc(GO:"extracellular space"), toLoc(GO:intracellular)) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

However, recent work provides direct evidence that PICALM can also modulate macroautophagy, via its role in SNARE endocytosis to clear tau aggregates [102]. PubMed:29758300

Appears in Networks:

complex(a(CHEBI:lipid), p(HGNC:MAPT)) increases a(HBP:"Tau aggregates") View Subject | View Object

Cytosolic tau is highest in density in membrane-rich axons and growth cones where lipid interaction with cytosolic tau may contribute to fibrillary tau aggregation [84]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Cytosol

complex(a(MESH:"Lipid Bilayers"), p(HGNC:MAPT)) association a(HBP:"Tau aggregates") View Subject | View Object

Furthermore, the membrane bilayer lipid can influence protein aggregation and subsequent tau pathology, with recent studies showing that tau binds to the membrane, which has subsequent effects on the formation of fibrillary tau aggregates [85,86]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(HBP:"Tau aggregates") View Subject | View Object

However, when tau becomes hyperphosphorylated, it detaches from microtubules and aggregates, resulting in depolymerization of microtubules and formation of insoluble tau deposits [40] PubMed:29758300

Appears in Networks:

complex(a(HBP:"Tau aggregates"), p(HBP:"20 S Proteasome")) hasComponent a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

In familial tauopathies, the mutation of MAPT seems to be the cause of tau aggregation, but in sporadic tauopathies (such as AD), the trigger of tau pathology is unclear. PubMed:26631930

Appears in Networks:

a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:"Tau aggregates") View Subject | View Object

Our previous study [23] had shown that trehalose induces autophagy in primary neurons and in an N2a cell model of tauopathy, and efficiently reduces the level of MAPT and MAPT aggregation. PubMed:30145931

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"methylene blue") decreases a(HBP:"Tau aggregates") View Subject | View Object

At the biochemical level, MB treatment altered Tau solubility, shifting the equilibrium towards more soluble Tau and reduced detergent-insoluble Tau by  35% in the pro-aggregant strain (Fig. 8A, quantitation in 8B), con- sistent with its anti-aggregation properties (31). PubMed:22611162

Appears in Networks:

a(PUBCHEM:25096749) decreases a(HBP:"Tau aggregates") View Subject | View Object

BSc3094 resulted in 40% decrease in the detergent-insoluble Tau (FA fraction) in pro-aggregant animals, PubMed:22611162

Appears in Networks:

p(HGNC:MAPT, var("p.Ile277Pro")) decreases a(HBP:"Tau aggregates") View Subject | View Object

In one set of C. elegans strains, we expressed the pathological FDTP-17 mutant DK280, which enhances aggregation, whereas the other set harbours, in addition to DK280, the proline substitutions I277P and I308P (PP), which act as b-sheet breakers and prevent aggregation (15). PubMed:22611162

Appears in Networks:

p(HGNC:MAPT, var("p.Ile308Pro")) decreases a(HBP:"Tau aggregates") View Subject | View Object

In one set of C. elegans strains, we expressed the pathological FDTP-17 mutant DK280, which enhances aggregation, whereas the other set harbours, in addition to DK280, the proline substitutions I277P and I308P (PP), which act as b-sheet breakers and prevent aggregation (15). PubMed:22611162

Appears in Networks:

p(HGNC:MAPT, var("p.Lys280del")) increases a(HBP:"Tau aggregates") View Subject | View Object

For this purpose, we focused on the well-characterized DK280 mutation (10–13), which specifically leads to aggregation-mediated toxicity. PubMed:22611162

Appears in Networks:

a(CHEBI:"sodium chlorate") decreases a(HBP:"Tau aggregates") View Subject | View Object

To test whether HSPGs also mediate BD Tau seeding, we titrated heparin and sodium chlorate, which inhibited seeding of all species (Fig. 8D). PubMed:25887395

Appears in Networks:

a(CHEBI:heparin) decreases a(HBP:"Tau aggregates") View Subject | View Object

To test whether HSPGs also mediate BD Tau seeding, we titrated heparin and sodium chlorate, which inhibited seeding of all species (Fig. 8D). PubMed:25887395

Appears in Networks:

complex(a(HBP:"Tau fibrils"), p(HGNCGENEFAMILY:Syndecans)) increases a(HBP:"Tau aggregates") View Subject | View Object

Heparan sulfate proteoglycans (HSPGs) are cell surface pro- teins that bind Tau fibrils and are required for their uptake and seeding (10). PubMed:25887395

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:MAPT), p(HGNC:MAPT)) increases a(HBP:"Tau aggregates") View Subject | View Object

Only Tau RD oligomers of n  3 increased luciferase signal, defining these assemblies as the minimal size sufficient for spontaneous cell uptake and seeding (Fig. 6C). PubMed:25887395

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:MAPT), p(HGNC:MAPT)) increases a(HBP:"Tau aggregates") View Subject | View Object

Next we analyzed fractions for seeding activity in the P301S- Nluc/Cluc HEK293 cell lines by a split-luciferase complemen- tation assay, comparing AD and control brains. Trimers and larger BD Tau assemblies induced intracellular aggregation, but not monomer or dimer. PubMed:25887395

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MeSH
Brain
MeSH
Alzheimer Disease

a(CHEBI:heparin) increases a(HBP:"Tau aggregates") View Subject | View Object

After 15 min of heparin exposure, we detected low but significant amounts of seed-compe- tent monomer, and much fewer larger assemblies (Figure 6A). PubMed:29988016

Appears in Networks:

a(PUBCHEM:100984821) increases a(HBP:"Tau aggregates") View Subject | View Object

Upon incubation with Lipofectamine, we were surprised to observe seeding by monomer and larger assemblies alike, whether FL WT or 2A. (Figure 1C,D). PubMed:29988016

Appears in Networks:

p(HGNC:MAPT) increases a(HBP:"Tau aggregates") View Subject | View Object

AD-derived M s that was purified, frozen, and re-purified by SEC exhibited seeding activ- ity exclusively in the monomer fraction (Figure 8E). By contrast, AD-derived M s incubated at RT formed seed-competent assemblies of increasing size (Figure 8E). PubMed:29988016

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, var("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

However Ms induced amyloid forma- tion, albeit more slowly than trimer or unfractionated fibrils (Figure 1F). PubMed:29988016

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Tau from control brain purified in the monomer fraction (Figure 8A), while tau from AD brain distributed across multiple fractions, corresponding to monomer and larger assem- blies (Figure 8B). PubMed:29988016

Appears in Networks:
Annotations
MeSH
Brain

a(PUBCHEM:10341154) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:10435235) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:11154925) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:11234052) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:11570805) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:11655119) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:156422) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:24756910) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:2746) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:3033825) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:4261) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:42640) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:447966) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:448537) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:4521392) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:46209426) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:4878) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:49806720) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:5311272) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:5318517) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:53340666) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:5833) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:6321424) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:71295844) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:71729974) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:9804992) increases a(HBP:"Tau aggregates") View Subject | View Object

Treatment with Givinostat (1.2 µM) lead to a nearly 7-fold increase in the fraction of ThS + cells (from ~ 12% to ~ 84%, Fig. S4A and B, blue lines) compared to the uninduced control, and 2.5-fold compared to the induced control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:9839311) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:9865515) increases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

a(PUBCHEM:9880) decreases a(HBP:"Tau aggregates") View Subject | View Object

Tab. 1A-B: Summary of the Tau aggregation modulators (inhibitors = 18 (A), stimulators = 10 (B)) which show decrease / increase in the amount of ThS + cells without affecting the expression level of TauRD∆K compared to the compound untreated control. PubMed:30640040

Appears in Networks:

act(p(FPLX:HDAC)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Conversely, compounds related to HDAC inhibition (16 of 20) led to enhanced Tau aggregation, suggesting that HDAC activity is important for suppressing aggregation PubMed:30640040

Appears in Networks:

act(p(FPLX:TGFB)) increases a(HBP:"Tau aggregates") View Subject | View Object

The dose response screening identified compounds related to the inhibition of 3 major targets led to inhibition of Tau aggregation: p38 MAPK (7 out of 8 compounds in the initial library), VEGFR1/2 (3 of 8) and TGF (3 of 10). PubMed:30640040

Appears in Networks:

act(p(HGNC:FLT1)) increases a(HBP:"Tau aggregates") View Subject | View Object

The dose response screening identified compounds related to the inhibition of 3 major targets led to inhibition of Tau aggregation: p38 MAPK (7 out of 8 compounds in the initial library), VEGFR1/2 (3 of 8) and TGF (3 of 10). PubMed:30640040

Appears in Networks:

act(p(HGNC:KDR)) increases a(HBP:"Tau aggregates") View Subject | View Object

The dose response screening identified compounds related to the inhibition of 3 major targets led to inhibition of Tau aggregation: p38 MAPK (7 out of 8 compounds in the initial library), VEGFR1/2 (3 of 8) and TGF (3 of 10). PubMed:30640040

Appears in Networks:

act(p(HGNC:MAPK14)) increases a(HBP:"Tau aggregates") View Subject | View Object

The dose response screening identified compounds related to the inhibition of 3 major targets led to inhibition of Tau aggregation: p38 MAPK (7 out of 8 compounds in the initial library), VEGFR1/2 (3 of 8) and TGF (3 of 10). PubMed:30640040

Appears in Networks:

a(CHEBI:"methylene blue") decreases a(HBP:"Tau aggregates") View Subject | View Object

For example, Fatouros et al. (68) tested several tau-aggregation inhibitor compounds such as methylene blue, a rhodanine derivative (bb14), and a phenylthiazolyl hydrazide derivative (BSc3094), which reduce the insoluble tau and partially suppress the Unc phenotype. PubMed:29191965

Appears in Networks:

a(HBP:"Phenylthiazolyl-hydrazide") decreases a(HBP:"Tau aggregates") View Subject | View Object

For example, Fatouros et al. (68) tested several tau-aggregation inhibitor compounds such as methylene blue, a rhodanine derivative (bb14), and a phenylthiazolyl hydrazide derivative (BSc3094), which reduce the insoluble tau and partially suppress the Unc phenotype. PubMed:29191965

Appears in Networks:

a(PUBCHEM:6475963) decreases a(HBP:"Tau aggregates") View Subject | View Object

For example, Fatouros et al. (68) tested several tau-aggregation inhibitor compounds such as methylene blue, a rhodanine derivative (bb14), and a phenylthiazolyl hydrazide derivative (BSc3094), which reduce the insoluble tau and partially suppress the Unc phenotype. PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Nonetheless, it is assumed that tau aggregation may be driven by phosphorylation at certain sites (95), whereas phosphorylation at other sites may inhibit aggregation (96). PubMed:29191965

Appears in Networks:

bp(GO:aging) increases a(HBP:"Tau aggregates") View Subject | View Object

Cortical neurons of Tg Tau P301S mice also show an in- crease in tau hyperphosphorylation and pSyk with age (Fig. 7). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
cerebral cortex neuron

a(CHEBI:"polyanionic polymer") increases a(HBP:"Tau aggregates") View Subject | View Object

Conversely, tau aggregation can be induced in vitro efficiently by polyanionic cofactors, regardless of phosphorylation PubMed:26631930

Appears in Networks:

tloc(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) increases a(HBP:"Tau aggregates") View Subject | View Object

In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles. PubMed:25374103

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association a(HBP:"Tau aggregates") View Subject | View Object

Abnormal Syk activation seems to fol- low tau hyperphosphorylation (S202) in the hippocampus of Tg P301S mice (Fig. 6), as well as the formation of MC1-tau pathological conformers (data not shown here but MC1 and pSyk colocalization were quantified below). PubMed:28877763

Appears in Networks:
Annotations
MeSH
Hippocampus

p(HGNC:MAPT, var("p.Pro301Ser")) increases a(HBP:"Tau aggregates") View Subject | View Object

Hippocampal neurons of Tg Tau P301S mice exhibit a high level of tau hyperphosphorylation (Fig. 4b) as well as an accumulation of pathogenic tau conformers (MC1, not shown) compared to WT littermates (Fig. 4a). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
hippocampal neuron

p(HGNC:SYK) association a(HBP:"Tau aggregates") View Subject | View Object

Most importantly, pathological tau species clearly colo- calize with pSyk (Y525/526) in hippocampal neurons (Fig. 4b). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
hippocampal neuron

p(HGNC:SYK) association a(HBP:"Tau aggregates") View Subject | View Object

We observed a colocalization between pSyk and pTau (S202) immuno- reactivities in cortical neurons. PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
cerebral cortex neuron

p(HGNC:SYK) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

In general, we found that neurons that exhibit a high level of pSyk immunoreactivity also demonstrate a higher level of tau pathogenic species whereas neurons that are weakly immunopositive for pSyk show less tau pathology (Figs. 9, 10, 11, 12 and 13). PubMed:28877763

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"polyanionic polymer") increases a(HBP:"Tau aggregates") View Subject | View Object

Tau aggregation could be accelerated by cofactors such as polyanions that compensate for the repulsive positive charges of tau PubMed:26631930

Appears in Networks:

bp(GO:aging) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

However, tau aggregates are also observed in the brains of some aged individuals with a condition known as primary age-related tauopathy (PART) PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain

complex(a(GO:microtubule), p(HGNC:MAPT)) negativeCorrelation a(HBP:"Tau aggregates") View Subject | View Object

This suggests that the stabilization of the microtubule-bound conformation of tau may delay tau aggregation PubMed:26631930

Appears in Networks:

complex(a(GO:microtubule), p(HGNC:MAPT)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

complex(a(MESH:RNA), p(HGNC:MAPT)) increases a(HBP:"Tau aggregates") View Subject | View Object

Nevertheless, the interaction of tau with RNA may induce tau aggregation and thus contribute to neurodegeneration PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(HBP:"Tau aggregates") View Subject | View Object

Notably, as aggregated tau in patients with a tauopathy or in transgenic mice invariably show hyperphosphorylation, and tau hyperphosphorylation precedes aggregation, phosphorylation has been assumed to drive tau aggregation PubMed:26631930

Appears in Networks:

p(HBP:"VQIINK motif") increases a(HBP:"Tau aggregates") View Subject | View Object

The two short hexapeptide motifs VQIINK and VQIVYK at the beginning of R2 and R3, respectively, show propensity for forming β‑sheet structures and are essential for tau aggregation, even though they comprise only a tiny fraction of the sequence PubMed:26631930

Appears in Networks:

p(HBP:"VQIINK motif") increases a(HBP:"Tau aggregates") View Subject | View Object

Disruption of these motifs (for example, by Pro mutations) abrogates the tendency for tau to aggregate; by contrast, strengthening the β‑structure with certain mutations (for instance, ΔK280 or P301L) accelerates tau aggregation both in vitro and in vivo PubMed:26631930

Appears in Networks:

p(HBP:"VQIVYK motif") increases a(HBP:"Tau aggregates") View Subject | View Object

The two short hexapeptide motifs VQIINK and VQIVYK at the beginning of R2 and R3, respectively, show propensity for forming β‑sheet structures and are essential for tau aggregation, even though they comprise only a tiny fraction of the sequence PubMed:26631930

Appears in Networks:

p(HBP:"VQIVYK motif") increases a(HBP:"Tau aggregates") View Subject | View Object

Disruption of these motifs (for example, by Pro mutations) abrogates the tendency for tau to aggregate; by contrast, strengthening the β‑structure with certain mutations (for instance, ΔK280 or P301L) accelerates tau aggregation both in vitro and in vivo PubMed:26631930

Appears in Networks:

p(HGNC:FKBP4) increases a(HBP:"Tau aggregates") View Subject | View Object

Notably, two proteins — 14‑3‑3ζ and immunophilin (also known as FKBP52 or FKBP4) — have also been shown to induce aggregation of recombinant tau in vitro, presumably by stabilizing an aggregation-prone conformation of tau. PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, frag("151_391")) increases a(HBP:"Tau aggregates") View Subject | View Object

One of these fragments was identified as tau151–391, which is prone to aggregation, as rats transgenic for this fragment develop neurofibrillary pathology; the identity of the other fragment remains unclear PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, frag("1_368")) increases a(HBP:"Tau aggregates") View Subject | View Object

The truncation of tau at Asn368 has been observed in human AD brains and in a P301S mouse model of tauopathy, in which it leads to the generation of a tau1–368 fragment that is prone to aggregation and shows compromised microtubule-assembly activity, possibly contributing to tau aggregation and neurodegeneration. PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, frag("1_421")) increases a(HBP:"Tau aggregates") View Subject | View Object

In human AD brains and in the Tg4510 tauopathy mouse model, full-length tau is cleaved by caspase 3 behind Asp421 to generate tau1–421, which is prone to aggregation and subsequent formation of NFTs PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, frag("258_360")) increases a(HBP:"Tau aggregates") View Subject | View Object

In a cellular model of tauopathy, cells expressing the ΔK280 repeat-domain-mutant tau show tau aggregation that depends on the stepwise proteolysis of the N‑terminal domain by a thrombin-like protease and of the C‑terminal domain by cathepsin L, generating a fragment (F3) that leads to robust aggregation in cell and animal models PubMed:26631930

Appears in Networks:
Annotations
MeSH
Tauopathies

p(HGNC:MAPT, frag("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

Truncation of tau prevents the formation of this structure and might thereby promote tau aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, frag("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

Truncation of tau could generate tau fragments with a higher tendency for aggregation (see below), probably owing to the disruption of the paperclip structure of tau, as described above. PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, frag("?")) increases a(HBP:"Tau aggregates") View Subject | View Object

Truncated tau fragments that contain the repeat domain have a higher tendency for aggregation, probably owing to the disruption of the usual paperclip structure PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 259)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 290)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 321)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 353)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Depending on the sites, the acetylation of tau could inhibit its degradation (for example, when at Lys163, Lys280, Lys281 or Lys369) or, by contrast, facilitate its degradation and suppress its phosphorylation and aggregation (for example, when at Lys259, Lys290, Lys321 or Lys353) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(GO:"protein peptidyl-prolyl isomerization")) increases a(HBP:"Tau aggregates") View Subject | View Object

Non-enzymatic post-translational modifications, including glycation, deamidation and isomerization, are detected in PHF-tau but not in normal tau. All of these modifications may facilitate tau aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:"non-enzymatic protein modifications")) increases a(HBP:"Tau aggregates") View Subject | View Object

Non-enzymatic post-translational modifications, including glycation, deamidation and isomerization, are detected in PHF-tau but not in normal tau. All of these modifications may facilitate tau aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:glycation)) increases a(HBP:"Tau aggregates") View Subject | View Object

Non-enzymatic post-translational modifications, including glycation, deamidation and isomerization, are detected in PHF-tau but not in normal tau. All of these modifications may facilitate tau aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Me, Lys)) decreases a(HBP:"Tau aggregates") View Subject | View Object

Lysine methylation is another endogenous post-translational modification of tau in the human brain, and in vitro studies have shown that methylation of tau suppresses its aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(OGlyco)) decreases a(HBP:"Tau aggregates") View Subject | View Object

In addition, O‑GlcNAcylation of tau can suppress tau aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(OGlyco)) decreases a(HBP:"Tau aggregates") View Subject | View Object

In AD, the O‑GlcNAcylation of tau is reduced — an effect that might contribute to the hyperphosphorylation and aggregation of tau PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Tyr)) increases a(HBP:"Tau aggregates") View Subject | View Object

In a line of the JNPL3 tauopathy mouse model, which expresses human 0N4R tau bearing the missense P301L mutation, the overall increase in Tyr phosphorylation of tau correlated with the formation of tau aggregates, suggesting that overall Tyr phosphorylation might contribute to tau aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Arg406Trp")) increases a(HBP:"Tau aggregates") View Subject | View Object

Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Asn279Lys")) increases a(HBP:"Tau aggregates") View Subject | View Object

Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Gly272Val")) increases a(HBP:"Tau aggregates") View Subject | View Object

Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Lys280del")) increases a(HBP:"Tau aggregates") View Subject | View Object

Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Lys280del")) increases a(HBP:"Tau aggregates") View Subject | View Object

Disruption of these motifs (for example, by Pro mutations) abrogates the tendency for tau to aggregate; by contrast, strengthening the β‑structure with certain mutations (for instance, ΔK280 or P301L) accelerates tau aggregation both in vitro and in vivo PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Lys280del")) increases a(HBP:"Tau aggregates") View Subject | View Object

In a cellular model of tauopathy, cells expressing the ΔK280 repeat-domain-mutant tau show tau aggregation that depends on the stepwise proteolysis of the N‑terminal domain by a thrombin-like protease and of the C‑terminal domain by cathepsin L, generating a fragment (F3) that leads to robust aggregation in cell and animal models PubMed:26631930

Appears in Networks:
Annotations
MeSH
Tauopathies

p(HGNC:MAPT, var("p.Pro301Leu")) increases a(HBP:"Tau aggregates") View Subject | View Object

Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Leu")) increases a(HBP:"Tau aggregates") View Subject | View Object

Disruption of these motifs (for example, by Pro mutations) abrogates the tendency for tau to aggregate; by contrast, strengthening the β‑structure with certain mutations (for instance, ΔK280 or P301L) accelerates tau aggregation both in vitro and in vivo PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, var("p.Val337Met")) increases a(HBP:"Tau aggregates") View Subject | View Object

Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930

Appears in Networks:

p(HGNC:YWHAZ) increases a(HBP:"Tau aggregates") View Subject | View Object

Notably, two proteins — 14‑3‑3ζ and immunophilin (also known as FKBP52 or FKBP4) — have also been shown to induce aggregation of recombinant tau in vitro, presumably by stabilizing an aggregation-prone conformation of tau. PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

act(p(HGNC:MTOR)) increases a(HBP:"Tau aggregates") View Subject | View Object

On the other hand, some evidence indicates that suppressing mTOR activity ameliorates AD cognitive defects by decreasing Abeta and tau pathology PubMed:30061532

Appears in Networks:

Out-Edges 71

a(HBP:"Tau aggregates") increases path(MESH:"Neurofibrillary Tangles") View Subject | View Object

NFTs are formed by accumulation of hyperphosphorylated tau protein[7, 8]. Tau is a microtubule-binding protein whose function is to stabilize microtubules and facilitate fast axonal transport. Once highly phosphorylated, tau dissociates from microtubules and is prone to aggregate, forming paired helical fi laments that aggregate into NFTs PubMed:24590577

Appears in Networks:

a(HBP:"Tau aggregates") increases path(MESH:"Neurofibrillary Tangles") View Subject | View Object

Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1). PubMed:24027553

Appears in Networks:
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Text Location
Review

a(HBP:"Tau aggregates") positiveCorrelation path(HBP:neurotoxicity) View Subject | View Object

Thrombin cleavage of the repeat domain construct yielded fragments that rapidly aggregated, which closely correlated with toxicity in cell culture (15). These fragments can also induce the aggregation of full-length tau (39). PubMed:24027553

Appears in Networks:
Annotations
Text Location
Review

a(HBP:"Tau aggregates") decreases act(p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

This may suggest that abnormal proteins themselves may interfere with proteasomal degradative processes. Indeed, in vitro aggregated paired helical filament tau could inhibit proteasome activity (69). PubMed:24027553

Appears in Networks:
Annotations
Text Location
Review

a(HBP:"Tau aggregates") positiveCorrelation a(MESH:Autophagosomes) View Subject | View Object

Electron microscopic analysis of brain tissue from confirmed AD cases revealed that AVs accumulated in dystrophic neurites and correlated with the presence of filamentous tau (79). However, this correlation was not quantified (79).Similar results were observed in mouse models of AD. PubMed:24027553

Appears in Networks:
Annotations
MeSH
Alzheimer Disease
Text Location
Review

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal transport") View Subject | View Object

Collectively, these studies indicate that inhibition of anterograde FAT represents a toxic effect common to all tau aggregates, regardless of isoform composition PubMed:27574109

Appears in Networks:

a(HBP:"Tau aggregates") association a(GO:"late endosome") View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") association a(GO:lysosome) View Subject | View Object

Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After extensive washing, monomeric and aggregated tau-Dylight were both detected within cells expressing the neuron-specific microtubule-associated protein MAP2, confirming that both forms of tau enter neurons PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Tau-Dylight was found predominantly within the somatic compartment of neurons (Figure 1A) PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

After a 4-hr incubation with extracellular tau, flow cytometry analysis (Figures 1B and 1C) revealed that 83% and 73% of dissociated cells contained monomeric or aggregated tau-Dylight, respectively, demonstrating that extracellular tau efficiently enters human neurons in culture PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Internalization of aggregated tau-pHrodo (Figure 2D) was also found to be concentration dependent (Figure 2E) PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

These kinetics of aggregated tau-pHrodo entry are similar to that of both lower concentrations of monomeric tau (2.5 nM) and of low-molecular weight (10-kDa) dextran-pHrodo (same molarity as monomeric tau samples; Figures S5A–S5C PubMed:29590627

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

a(HBP:"Tau aggregates") association a(GO:"early endosome") View Subject | View Object

As early as 1 hr after the addition of extracellular tau, monomeric and aggregated tau-Dylight were co-localized in EEA1+ early endosomes PubMed:29590627

Appears in Networks:

a(HBP:"Tau aggregates") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD. PubMed:23528736

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"Tau aggregates") increases path(MESH:Tauopathies) View Subject | View Object

Tauopathies are a family of neurodegenerative disorders characterized by the appearance of aggregates of the microtubule-associating protein, tau. PubMed:21882945

Appears in Networks:

a(HBP:"Tau aggregates") increases a(GO:"neurofibrillary tangle") View Subject | View Object

These share a common histopathological hallmark known as neurofibrillary tangles (NFTs) that consist of an accumulation of fibrillar tau deposits initially produced from tau protein aggregation (Ballatore et al., 2007) PubMed:28420982

Appears in Networks:
Annotations
Confidence
High

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Additionally, studies have discovered that aggregated tau inhibits fast axonal transport in the anterograde direction at all physiological tau levels, whereas tau monomers have had no effect in either direction (LaPointe et al., 2009; Morfini et al., 2009) PubMed:28420982

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex

a(HBP:"Tau aggregates") association bp(MESH:"Neuronal Plasticity") View Subject | View Object

A recent study showed that neuronal networks facilitate cell-to-cell transfer of tau via synapses; using a microfluidic device they demonstrated that decreasing synaptic connections weakens tau transfer and the subsequent aggregation on the acceptor cell (Calafate et al., 2015) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Low
MeSH
Entorhinal Cortex

a(HBP:"Tau aggregates") association sec(p(HGNC:MAPT)) View Subject | View Object

Significantly, evidence suggests that tau secretion is partly mediated by ectosomal vesicles and that pathological tau accumulation in cells leads to a deviation toward tau secretion by exosomal vesicles (Dujardin et al., 2014a) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Exosomes
MeSH
Alzheimer Disease

a(HBP:"Tau aggregates") association a(CHEBI:dextran) View Subject | View Object

Evidence shows that tau aggregates colocalize with dextran and HeLa cells, hinting that internalized aggregates are transported in endosomal vesicles and passed through the endosomal pathway to lysosomes (Wu et al., 2013) PubMed:28420982

Appears in Networks:
Annotations
MeSH
Extracellular Space
Confidence
High
MeSH
Exosomes
MeSH
Alzheimer Disease

a(HBP:"Tau aggregates") association p(HGNC:HDAC6) View Subject | View Object

While a direct role of XAP2 in tau pathogenesis has not been described, studies have shown that XAP2 is activated by histone deacetylase (HDAC) 6, which has been linked to pathogenic tau (Kekatpure et al., 2009; Cook et al., 2012; Selenica et al., 2014). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

a(HBP:"Tau aggregates") increases path(MESH:Tauopathies) View Subject | View Object

The pathological accumulation of tau is a hallmark in several neurodegenerative disorders collectively termed tauopathies (Kovacs, 2015); a series of diseases including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease, and chronic traumatic encephalopathy (CTE; Guo et al., 2017). PubMed:29311797

Appears in Networks:

a(HBP:"Tau aggregates") association bp(GO:"glucocorticoid receptor signaling pathway") View Subject | View Object

In addition, XAP2 coordinates with Hsp90 to regulate glucocorticoid receptor signaling (Laenger et al., 2009), which has also been implicated in the production of pathogenic tau (Pinheiro et al., 2016). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

a(HBP:"Tau aggregates") association p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

TNT1 also co-localizes in tissue with the phospho-epitope defined by the AT8 antibody, indicating that PAD exposure represents an early event in AD pathology PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") hasComponent a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:

a(HBP:"Tau aggregates") hasComponent a(HBP:"Tau fibrils") View Subject | View Object

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) View Subject | View Object

The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167]. PubMed:26751493

Appears in Networks:

tloc(a(HBP:"Tau aggregates"), fromLoc(MESH:Neurons), toLoc(MESH:Neurons)) positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [166,167]. PubMed:26751493

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

We discovered that aggregated tau inhibits FAT only in the anterograde direction at physiological tau levels, whereas tau monomers had no effect on FAT in either direction, even at concentrations of tau >10-fold higher than PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21] PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") increases act(p(HGNC:PPP1CA)) View Subject | View Object

However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21] PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") increases act(p(HGNC:GSK3A)) View Subject | View Object

However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21] PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") association p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

TNT1 also co-localizes in tissue with the phospho-epitope defined by the AT8 antibody, indicating that PAD exposure represents an early event in AD pathology PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") positiveCorrelation p(MGI:Crhr1) View Subject | View Object

CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). PubMed:25125464

Appears in Networks:
Annotations
Uberon
hippocampal formation

a(HBP:"Tau aggregates") negativeCorrelation p(HGNC:OTUB1) View Subject | View Object

Interestingly, Otub1 expression is gradually downregulated with increasing Tau-seeded Tau aggregation (Fig. S4a), which could be considered as a protective mechanism. PubMed:28083634

Appears in Networks:
Annotations
MeSH
Hippocampus

a(HBP:"Tau aggregates") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

Appears in Networks:

a(HBP:"Tau aggregates") association bp(GO:autophagy) View Subject | View Object

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy. PubMed:29758300

Appears in Networks:

a(HBP:"Tau aggregates") association complex(a(MESH:"Lipid Bilayers"), p(HGNC:MAPT)) View Subject | View Object

Furthermore, the membrane bilayer lipid can influence protein aggregation and subsequent tau pathology, with recent studies showing that tau binds to the membrane, which has subsequent effects on the formation of fibrillary tau aggregates [85,86]. PubMed:29758300

Appears in Networks:

a(HBP:"Tau aggregates") increases p(HBP:"Tau aggregates", pmod(Ub)) View Subject | View Object

This finding suggests that neuropil threads may extend at both ends: Tau may aggregate and deposit first, followed by its ubiquitination. PubMed:22908190

Appears in Networks:

a(HBP:"Tau aggregates") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

In vitro experiments further showed that aggregated (recombinant) tau—but not nonaggregated (monomeric) tau—can inhibit the proteasome activity. PubMed:22908190

Appears in Networks:

a(HBP:"Tau aggregates") increases path(HBP:proteotoxicity) View Subject | View Object

For this purpose, we focused on the well-characterized DK280 mutation (10–13), which specifically leads to aggregation-mediated toxicity. PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") decreases bp(GO:"axonal transport") View Subject | View Object

Aberrant phosphorylation and aggregation of Tau have been linked to axonal transport problems, synaptic malfunction and degeneration (6). PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") decreases bp(GO:"synaptic signaling") View Subject | View Object

Aberrant phosphorylation and aggregation of Tau have been linked to axonal transport problems, synaptic malfunction and degeneration (6). PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") decreases bp(GO:"synaptic signaling") View Subject | View Object

Resistance to aldicarb can arise from either a pre- or a post-synaptic perturbation, whereas resistance to levamisole typically indicates a post-synaptic defect (50). Animals of the pro-aggregant strain displayed a mild resist- ance to aldicarb, producing a paralysis profile intermediate between the sensitive wild-type N2 and the resistant rab-3(js49) strain, which we used as controls (Fig. 5A). PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") decreases bp(GO:"maintenance of synapse structure") View Subject | View Object

Aberrant phosphorylation and aggregation of Tau have been linked to axonal transport problems, synaptic malfunction and degeneration (6). PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") decreases p(UNIPROT:O02495) View Subject | View Object

This indicated that SNB-1 failed to properly accumulate at the presynaptic termini of young adult pro-aggregant worms. PubMed:22611162

Appears in Networks:
Annotations
MeSH
Presynaptic Terminals
MeSH
Neurons

a(HBP:"Tau aggregates") decreases bp(GO:"intracellular distribution of mitochondria") View Subject | View Object

We crossed WyEx2709 into the pro-aggregant strain (resulting in strain BR6011) and discov- ered that this regular mitochondrial distribution was distorted. PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") decreases bp(GO:"axonal transport of mitochondrion") View Subject | View Object

The velocity of mitochondrial transport in the pro-aggregant strain was lower than in wild-type (mean + SD ¼ 171 + 111 versus 256 + 117 nm/s), whereas the anti-aggregant strain (194 + 131 nm/ s) did not substantially differ from wild- type (Fig. 7D). PubMed:22611162

Appears in Networks:

a(HBP:"Tau aggregates") causesNoChange bp(GO:"cell death") View Subject | View Object

In our hands, these aggregated tau species formed in different conditions did not show any significant release of LDH when applied on the differentiated SH-SY5Y cells (Supplementary Fig. 8A), and they did not show a significant reduction in cell viability by the MTTassay (Supplementary Fig. 8B). PubMed:28528849

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SK-N-SH

a(HBP:"Tau aggregates") causesNoChange a(GO:membrane) View Subject | View Object

In our hands, these aggregated tau species formed in different conditions did not show any significant release of LDH when applied on the differentiated SH-SY5Y cells (Supplementary Fig. 8A), and they did not show a significant reduction in cell viability by the MTTassay (Supplementary Fig. 8B). PubMed:28528849

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SK-N-SH

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Tau from control brain purified in the monomer fraction (Figure 8A), while tau from AD brain distributed across multiple fractions, corresponding to monomer and larger assem- blies (Figure 8B). PubMed:29988016

Appears in Networks:
Annotations
MeSH
Brain

a(HBP:"Tau aggregates") increases bp(GO:"cell killing") View Subject | View Object

As shown before, Tau aggregation (on the level of oligomeric and/or fibril aggregates) is toxic for cells. PubMed:30640040

Appears in Networks:

a(HBP:"Tau aggregates") decreases act(a(GO:synapse)) View Subject | View Object

One exception is the report of the accumulation of tau aggregates in presynaptic boutons in transgenic mice, whereby it induces synaptic dysfunction and loss of presynapses (77). PubMed:29191965

Appears in Networks:
Annotations
MeSH
Presynaptic Terminals

a(HBP:"Tau aggregates") decreases a(GO:presynapse) View Subject | View Object

One exception is the report of the accumulation of tau aggregates in presynaptic boutons in transgenic mice, whereby it induces synaptic dysfunction and loss of presynapses (77). PubMed:29191965

Appears in Networks:
Annotations
MeSH
Presynaptic Terminals

a(HBP:"Tau aggregates") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Nonetheless, it is assumed that tau aggregation may be driven by phosphorylation at certain sites (95), whereas phosphorylation at other sites may inhibit aggregation (96). PubMed:29191965

Appears in Networks:

a(HBP:"Tau aggregates") increases a(GO:"neurofibrillary tangle") View Subject | View Object

In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles. PubMed:25374103

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HBP:"Tau aggregates") association p(HGNC:SYK) View Subject | View Object

Most importantly, pathological tau species clearly colo- calize with pSyk (Y525/526) in hippocampal neurons (Fig. 4b). PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
hippocampal neuron

a(HBP:"Tau aggregates") association p(HGNC:SYK) View Subject | View Object

We observed a colocalization between pSyk and pTau (S202) immuno- reactivities in cortical neurons. PubMed:28877763

Appears in Networks:
Annotations
Cell Ontology (CL)
cerebral cortex neuron

a(HBP:"Tau aggregates") positiveCorrelation p(HGNC:SYK) View Subject | View Object

In general, we found that neurons that exhibit a high level of pSyk immunoreactivity also demonstrate a higher level of tau pathogenic species whereas neurons that are weakly immunopositive for pSyk show less tau pathology (Figs. 9, 10, 11, 12 and 13). PubMed:28877763

Appears in Networks:
Annotations
MeSH
Neurons

a(HBP:"Tau aggregates") association p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Abnormal Syk activation seems to fol- low tau hyperphosphorylation (S202) in the hippocampus of Tg P301S mice (Fig. 6), as well as the formation of MC1-tau pathological conformers (data not shown here but MC1 and pSyk colocalization were quantified below). PubMed:28877763

Appears in Networks:
Annotations
MeSH
Hippocampus

a(HBP:"Tau aggregates") increases path(HBP:Neurodegeneration) View Subject | View Object

In addition, the aggregates may occupy space in the cell and thus directly interfere with axonal transport, leading to neurodegeneration PubMed:26631930

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

a(HBP:"Tau aggregates") negativeCorrelation complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

This suggests that the stabilization of the microtubule-bound conformation of tau may delay tau aggregation PubMed:26631930

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation bp(GO:aging) View Subject | View Object

However, tau aggregates are also observed in the brains of some aged individuals with a condition known as primary age-related tauopathy (PART) PubMed:26631930

Appears in Networks:
Annotations
MeSH
Brain

a(HBP:"Tau aggregates") decreases bp(GO:"microtubule polymerization") View Subject | View Object

Tau aggregation decreases levels of soluble functional tau, which may result in microtubule disassembly as well PubMed:26631930

Appears in Networks:

a(HBP:"Tau aggregates") decreases act(a(MESH:Neurons)) View Subject | View Object

In the longer term, however, these tau aggregates may sequester other cell components, finally compromising neuronal functions PubMed:26631930

Appears in Networks:

a(HBP:"Tau aggregates") decreases bp(GO:"axonal transport") View Subject | View Object

In addition, the aggregates may occupy space in the cell and thus directly interfere with axonal transport, leading to neurodegeneration PubMed:26631930

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.