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Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers v1.0.0

This document contains the bel code for the Article Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers by De Felice et al

TAU and Interaction Partners v1.2.5

TAU Interactions Section of NESTOR

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

In-Edges 66

p(HGNC:ESR1) association p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

To confirm the localization of ERα in NFTs, double fluorescence staining with antibodies to ERα and hyperphosphorylated tau (PHF-1) revealed that ERα -positive NFTs were also positive for PHF-1 (Fig. 2A–F). PubMed:26837465

p(HGNC:MAPT) hasVariant p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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p(HGNC:CHRNA7) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

p(HGNC:CHRNA4) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

act(p(HGNC:CHRM1)) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

It has been shown that activation of M1 receptors decreases tau hyperphosphorylation via activation of PKC and inhibition of GSK-3β PubMed:26813123

p(FPLX:CHRN) negativeCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Possible factors such as amyloid peptide accumulation, hyperphosphorylation of tau protein, oxidative stress, and modification of cell membrane during the development of AD may be related to decreased protein levels of nAChRs (Farooqui et al 1995; Smith et al 1996) PubMed:11230871

a(MESH:"Neurofibrillary Tangles") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In conjunction with the formation of neurofibrillary tangles, the synthesis of the tau protein increases, and it undergoes an abnormal posttranslational modification characterized by hyperphosphorylation PubMed:14556719

a(CHEBI:LY294002) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, the presence of large extracellular aggregates in NU1-treated cultures (Fig. 5N) suggests that the antibody effectively sequesters ADDLs and prevents their interactions with neurons (Fig. 5O). No inhibition of ADDL binding was associated with PP1 and LY294002 (Fig. 5H, I, K and L, respectively), but both kinase inhibitors effectively blocked ADDL-induced tau hyperphosphorylation (Fig. 5G and J). PubMed:17403556

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

These results confirm that the tau hyperphosphorylation stimulated by soluble ADDL preparations is indeed oligomer-induced. Tau hyperphosphorylation induced by 10M Abeta fibrils (Fig. 3N) was partially blocked (Fig. 3O), consistent with shared epitopes between oligomers and fibrils. PubMed:17403556

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Importantly, pre-incubation of AD brain extracts with NU1 significantly blocked the increase in Thr231 phosphotau immunofluorescence (Fig. 6G), establishing the tau hyperphosphorylation was induced by Abeta oligomers in the AD brain extracts. NU1 also prevented the binding of brain-derived ADDLs to synaptic hot-spots (Fig. 6H and I). In NU1-treated cultures, the presence of large extracellular aggregates indicates that the antibody sequesters ADDLs and prevents their interactions with neurons (Fig. 6I). PubMed:17403556

a(MESH:"4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, the presence of large extracellular aggregates in NU1-treated cultures (Fig. 5N) suggests that the antibody effectively sequesters ADDLs and prevents their interactions with neurons (Fig. 5O). No inhibition of ADDL binding was associated with PP1 and LY294002 (Fig. 5H, I, K and L, respectively), but both kinase inhibitors effectively blocked ADDL-induced tau hyperphosphorylation (Fig. 5G and J). PubMed:17403556

complex(a(HBP:"amyloid-beta derived diffusible ligands"), p(HGNC:MAPT)) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Inhibition occurred even though ADDLs were still bound to cell surfaces, indicating that those kinases are involved in signal transduction coupling between ADDL binding and tau hyperphosphorylation. PubMed:17403556

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

AD brains could induce AD-type tau hyperphosphorylation. Consistent with the results obtained with synthetic ADDLs, we found that treatment of mature hippocampal neuronal cultures with a soluble AD brain extract led to a significant increase in P231 tau phosphorylation (Fig. 6D) compared to cultures treated with a non-AD brain extract (Fig. 6A). PubMed:17403556

complex(p(FPLX:HSP90), p(HGNC:FKBP5)) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

This model is consistent with the data that hyperphosphorylated tau appears to be specifically selected for degradation by some chaperone machines, such as the Hsp90–FKBP51 complex, without effects on normal tau [132,136]. PubMed:21882945

complex(p(HGNC:HSPB1), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Hsp27 has emerged as a potential target for tau regulation based on early findings that it preferentially binds to phosphorylated and hyperphosphorylated tau and promotes their clearance [125,126] PubMed:21882945

a(HBP:EC102) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

The Hsp90 N-terminal domain inhibitor, EC102, was used to demonstrate degradation of hyperphosphorylated pathologically relevant tau in cells (Dickey et al., 2007a). PubMed:29311797

p(FPLX:HSP90) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice. PubMed:29311797

act(p(HGNC:GSK3B)) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

For example, ongoing inflammation can trigger various cell stress-response pathways, including overexpression of the secreted glycoprotein Dickopff-1 (DKK-1). DKK-1 up-regulates GSK-3β activity, promotes tau hyper-phosphorylation, NFT formation and neuronal degeneration. Thus, DKK-1 inhibits Wnt signalling in a manner similar to Aβ, and thereby fosters a self-sustaining feedback loop resulting in cellular injury PubMed:18494933

a(HBP:"Tubastatin A") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

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act(a(HBP:"advanced glycation end product")) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1μg/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3β (GSK-3β) to reverse tau hyperphosphorylation directly. PubMed:25987199

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bp(MESH:"Hot Temperature") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

>8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain PubMed:8226987

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bp(MESH:"Oxidative Stress") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

>8 phosphates per tau molecules (vs 2 in adult healthy brain); can also be increased during development, hibernation and temperature, heat and oxydative stress These phosphorylated states are detected by specific antibodies and are targets of proline-directed kinases (SP motifs), non-proline kinases (KXGS motif) Weakens tau-MT interaction especially S261 in R1 and S214 in proline-rich domain PubMed:8226987

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act(p(HGNC:CDK5), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. PubMed:25001178

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p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) negativeCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

These results are in accord with our previous study showing that Tau hyperphosphorylation is associated with a decrease in its O-GlcNAcylation level. A recent observation argues for the hypothesis that O-GlcNAcylation occurs first and that its modification reflects on the phosphorylation status. PubMed:19732809

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act(p(HGNC:PPP1CA)) directlyDecreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. PubMed:25001178

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p(MGI:Itpkb) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. PubMed:24401760

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a(PUBCHEM:5757) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, estradiol has been shown to inhibit tau hyperphosphorylation and can also modulate glycogen synthase kinase-3β (GSK-3β) activity, a kinase that is involved in tau phosphorylation. Estradiol deactivates GSK-3β by inducing its phosphorylation, thereafter reducing tau phosphorylation. PubMed:30444369

act(p(FPLX:PPP2)) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In Alzheimer's disease, inhibition of PP2A activity by SET leads to hyper phosphorylation of the Tau protein [47]. PubMed:23454242

complex(GO:"protein phosphatase type 2A complex") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

A key function of PP2A is thought to dephosphorylate the hyperphosphorylated Tau protein PubMed:19277525

p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Previous investigations indicate that specific dephosphorylation of Tau appeared to be mediated by the B family of regulatory subunits PubMed:19277525

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Neuronally overexpressed GSK-3β was demonstrated to hyperphosphorylate tau protein in vivo in the brain and spinal cord of double- transgenic mice (Spittaels et al., 2000) thereby reducing the amount of protein tau associated with microtubules by 50% (Spittaels et al., 2000). PubMed:12428809

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Further experiments based on the injection of a PP2A inhibitor in the rat hippocampus demon- strated tau hyper-phosphorylation, and learning and memory deficits [49, 50]. PubMed:22299660

Annotations
MeSH
Hippocampus

act(p(FPLX:PPP2)) negativeCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Studies in transgenic mice and in cell cultures have shown a connection between PP2A loss of function and tau hyper-phosphorylation and aggregation into PHF. PubMed:22299660

p(HGNC:SQSTM1) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

For example, Babu et al. has shown that p62−/− knockout mice have increased levels of hyperphosphorylated tau, reduction of synaptophysin and changes in short term memory compared to p62+/− [54] PubMed:29758300

a(GO:"neurofibrillary tangle") association p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Neurofibrillary tangles composed of tau proteins in a hyperphosphorylated state are rarely observed in abundance except in AD and a limited number of aging-related tauopathies. PubMed:22908190

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

Recently, it has been shown that soluble Ab oligomers isolated from AD cortex can induce tau hyperphosphorylation at AD-relevant epitopes and subsequent neuritic degeneration (Jin et al. 2011). PubMed:22908190

complex(p(HGNC:HSPA8), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), p(HGNC:STUB1)) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

On the other hand, it has been reported that the E3 ligase CHIP (carboxyl terminus of the Hsc70-interacting protein) binds to tau and is involved in the degradation of abnormal forms of tau, including insoluble tau and hyperphosphorylated tau, coordinately with Hsp70 (Petrucelli et al. 2004; Dickey et al. 2006). PubMed:22908190

p(FPLX:HSP90) regulates deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Recent data suggest that a critical mediator of refolding or clearance of hyperphosphorylated tau is via the HSP70/HSP90 heat shock pathways in which a specific E3 ubiquitin ligase, CHIP (carboxy terminus Hsp70 interacting protein), can recognize and target for degradation abnormal but not normal tau molecules [14–16]. PubMed:25374103

p(HGNC:STUB1) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Recent data suggest that a critical mediator of refolding or clearance of hyperphosphorylated tau is via the HSP70/HSP90 heat shock pathways in which a specific E3 ubiquitin ligase, CHIP (carboxy terminus Hsp70 interacting protein), can recognize and target for degradation abnormal but not normal tau molecules [14–16]. PubMed:25374103

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases tloc(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) 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

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

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

p(HGNC:MAPT, var("p.Pro301Ser")) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

p(HGNC:MAPT, var("p.Pro301Ser")) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Cortical neurons of Tg Tau P301S mice also exhibit an increased level of tau hyperphosphorylation (Fig. 5b) compared to wild-type littermates (Fig. 5a). PubMed:28877763

act(p(HGNC:SYK)) 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

p(HGNC:MAPT, pmod(NGlyco)) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Furthermore, N‑glycosylation may facilitate tau hyperphosphorylation, as it suppresses the dephosphorylation and accelerates the phosphorylation of tau, probably because it changes the conformation of tau PubMed:26631930

p(HGNC:MAPT, pmod(OGlyco)) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

p(HGNC:MAPT, var("p.Lys280del")) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

The pro-aggregant mouse lines developed AD‑like features (including missorting of tau into the somatodendritic compartment, tau conformational changes, tau hyperphosphorylation, NFTs and cognitive deficits), whereas the anti-aggregant lines show almost no pathology PubMed:26631930

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

a(CHEBI:"advanced glycation end-product") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

AGEs induce tau hyperphosphorylation, memory deterioration, decline of synaptic proteins, and impairment of long-term potentiation in rats [10]. PubMed:27288790

a(CHEBI:"reactive oxygen species") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Higher levels of ROS biomarkers are characteristic of AD patients in clinical and preclinical studies, resulting in the alteration of membrane proper- ties, such as fluidity, ion transport, enzyme activities, protein cross- linking, tau protein hyperphosphorylation, autophagic dysfunction and eventually neuron cell death [20]. PubMed:27288790

a(CHEBI:"mTOR inhibitor") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Again, rapamycin and rapalogs protect against toxicity produced by a number of misfolded proteins encompassing alpha synuclein, TDP43, and hyperphosphorylated tau PubMed:30061532

a(CHEBI:sirolimus) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Again, rapamycin and rapalogs protect against toxicity produced by a number of misfolded proteins encompassing alpha synuclein, TDP43, and hyperphosphorylated tau PubMed:30061532

p(HGNC:CDK5) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Both administration of amphetamines and stimulation of D1R induce a significant increase of CDK5 gene expression and protein levels, which, at molecular level, associates with increased dendritic spine density and hyper-phosphorylation of the cytoskeletal tau protein PubMed:30061532

act(p(HGNC:MTOR)) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

For instance, an increased mTOR activity correlates with accumulation of Abeta and hyperphosphorylated tau in AD brains PubMed:30061532

path(MESH:"Frontotemporal Dementia") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

path(MESH:"Lewy Body Disease") association p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In addition, most DLB patients show most features of AD (i.e., hyperphosphorylated tau deposits and A beta) to various extents PubMed:30061532

path(MESH:Schizophrenia) positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

Out-Edges 47

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association p(HGNC:ESR1) View Subject | View Object

To confirm the localization of ERα in NFTs, double fluorescence staining with antibodies to ERα and hyperphosphorylated tau (PHF-1) revealed that ERα -positive NFTs were also positive for PHF-1 (Fig. 2A–F). PubMed:26837465

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation p(HGNC:CHRNA7) View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation p(HGNC:CHRNA4) View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) negativeCorrelation p(FPLX:CHRN) View Subject | View Object

Possible factors such as amyloid peptide accumulation, hyperphosphorylation of tau protein, oxidative stress, and modification of cell membrane during the development of AD may be related to decreased protein levels of nAChRs (Farooqui et al 1995; Smith et al 1996) PubMed:11230871

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD brains could induce AD-type tau hyperphosphorylation. Consistent with the results obtained with synthetic ADDLs, we found that treatment of mature hippocampal neuronal cultures with a soluble AD brain extract led to a significant increase in P231 tau phosphorylation (Fig. 6D) compared to cultures treated with a non-AD brain extract (Fig. 6A). PubMed:17403556

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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(HBP:HBP00006) View Subject | View Object

The HMW tau species from the AD brain were highly phosphorylated compared with those from control brain (Fig. 6m). PubMed:26458742

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases tloc(p(HGNC:MAPT), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Phosphatase treatment dephosphorylated tau in rTg4510 brain extract (Fig. 7d) without changing HMW tau levels (Fig. 7e), resulting in a significant reduction of cellular uptake of tau (Fig. 7f). PubMed:26458742

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. PubMed:24401760

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases a(GO:microtubule) View Subject | View Object

Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation. Using genetic screen, a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. PubMed:23487739

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) negativeCorrelation p(HGNC:MAPT, pmod(HBP:"O-GlcNAcylation")) View Subject | View Object

These results are in accord with our previous study showing that Tau hyperphosphorylation is associated with a decrease in its O-GlcNAcylation level. A recent observation argues for the hypothesis that O-GlcNAcylation occurs first and that its modification reflects on the phosphorylation status. PubMed:19732809

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(GO:"neurofibrillary tangle") View Subject | View Object

Upon hyperphosphorylation, the protein Tau has a strong tendency to polymerize into neurofibrillary tangles in the brain, a hallmark of Alzheimer’s disease PubMed:19277525

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"microtubule polymerization") View Subject | View Object

The excessive accumulation of phosphate groups in tau is associated with its altered capacity in promoting microtubule assembly and stability [4-6]. PubMed:22299660

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

Studies in transgenic mice and in cell cultures have shown a connection between PP2A loss of function and tau hyper-phosphorylation and aggregation into PHF. PubMed:22299660

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) 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

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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases bp(GO:"microtubule depolymerization") 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association a(GO:"neurofibrillary tangle") View Subject | View Object

Neurofibrillary tangles composed of tau proteins in a hyperphosphorylated state are rarely observed in abundance except in AD and a limited number of aging-related tauopathies. PubMed:22908190

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"microtubule polymerization") View Subject | View Object

Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits. PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases tloc(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) 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

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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association act(p(HGNC:SYK)) 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

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

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

First, hyperphosphorylation of tau might induce tau missorting from axons to the somatodendritic compartment, which can cause synaptic dysfunction PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(MESH:"Dendritic Spines")) View Subject | View Object

Hyperphosphorylation, mutations and overexpression of tau can drive the mislocalization of tau into postsynaptic spines, resulting in synaptic dysfunction PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) 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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases complex(p(HGNC:MAPK8IP1), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

For example, hyperphosphorylated tau but not unphosphorylated tau can interact with the kinesin-associated protein JUN N‑terminal kinase-interacting protein 1 (JIP1) and thus impair the formation of the kinesin complex,which mediates axonal transport PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases complex(p(HGNC:MAPK8IP1), p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

For instance, hyperphosphorylated tau can interact with JIP1 and thus impair the formation of kinesin complex PubMed:26631930

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

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits. PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"axonal transport") View Subject | View Object

Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits. PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases complex(GO:"filamentous actin") View Subject | View Object

In a Drosophila melanogaster model of tauopathy, the hyperphosphorylation of tau led to the abnormal alignment and accumulation of F‑actin filaments, and thereby induced neurodegeneration PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases path(HBP:Neurodegeneration) View Subject | View Object

In a Drosophila melanogaster model of tauopathy, the hyperphosphorylation of tau led to the abnormal alignment and accumulation of F‑actin filaments, and thereby induced neurodegeneration PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases act(a(GO:synapse)) View Subject | View Object

Hyperphosphorylation, mutations and overexpression of tau can drive the mislocalization of tau into postsynaptic spines, resulting in synaptic dysfunction PubMed:26631930

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) association path(MESH:"Lewy Body Disease") View Subject | View Object

In addition, most DLB patients show most features of AD (i.e., hyperphosphorylated tau deposits and A beta) to various extents PubMed:30061532

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Frontotemporal Dementia") View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:Schizophrenia) View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation p(HGNC:CDK5) View Subject | View Object

Both administration of amphetamines and stimulation of D1R induce a significant increase of CDK5 gene expression and protein levels, which, at molecular level, associates with increased dendritic spine density and hyper-phosphorylation of the cytoskeletal tau protein PubMed:30061532

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.