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PubMed: 28877763

Title
Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.
Journal
Acta neuropathologica communications
Volume
5
Issue
None
Pages
69
Date
2017-09-06
Authors
Ait-Ghezala G | Beaulieu-Abdelahad D | Crawford F | Mouzon B | Mullan M | Paris D | Schweig JE | Yao H

Evidence 1440c761d6
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Interestingly, Syk upregulation in SH-SY5Y cells leads to a significant increase (1.7-fold) in phosphorylated tau at Y18 (Fig. 14c, p < 0.01) and at S396/404 (Fig. 14d, 3-fold, p < 0.0001) compared to control cells. Total tau levels are also significantly increased following Syk overexpression (Fig. 14e, 4.2-fold, p < 0.0001).

p(MGI:Mapt) positiveCorrelation p(MGI:Syk) View Subject | View Object

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p(MGI:Mapt, pmod(Ph, Ser, 396)) positiveCorrelation p(MGI:Syk) View Subject | View Object

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p(MGI:Mapt, pmod(Ph, Ser, 404)) positiveCorrelation p(MGI:Syk) View Subject | View Object

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p(MGI:Mapt, pmod(Ph, Tyr, 18)) positiveCorrelation p(MGI:Syk) View Subject | View Object

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p(MGI:Syk) positiveCorrelation p(MGI:Mapt, pmod(Ph, Tyr, 18)) View Subject | View Object

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p(MGI:Syk) positiveCorrelation p(MGI:Mapt, pmod(Ph, Ser, 396)) View Subject | View Object

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p(MGI:Syk) positiveCorrelation p(MGI:Mapt, pmod(Ph, Ser, 404)) View Subject | View Object

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p(MGI:Syk) positiveCorrelation p(MGI:Mapt) View Subject | View Object

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Evidence d78a59cba2
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We found an increase in Syk activation in DNs surrounding Aβ deposits as well as in neurons displaying an accumulation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was observed in brain sections from a non-demented control

p(HGNC:MAPT, pmod(Ph, Tyr, 18)) positiveCorrelation p(HGNC:SYK, pmod(Ph)) View Subject | View Object

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p(HGNC:SYK, pmod(Ph)) positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

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p(HGNC:SYK, pmod(Ph)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

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path(MESH:"Plaque, Amyloid") positiveCorrelation p(HGNC:SYK, pmod(Ph)) View Subject | View Object

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Evidence 5ee37709c5
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Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species.

p(MGI:Mapt, pmod(Ph, Ser, 301)) positiveCorrelation p(MGI:Syk) View Subject | View Object

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Annotations
Uberon
cerebral cortex
Uberon
hippocampal formation

p(MGI:Syk) positiveCorrelation p(MGI:Mapt, pmod(Ph, Ser, 301)) View Subject | View Object

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Uberon
cerebral cortex
Uberon
hippocampal formation

Evidence a0e4a6c9b1
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The upregulation of Syk activation observed in the brains of Tg APPsw and Tg PS1/APPsw is mainly attributable to pSyk accumulations in dystrophic neurites that are associated with Aβ plaques and increase with age and Aβ burden.

p(MGI:Syk, pmod(Ph)) positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

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path(MESH:"Plaque, Amyloid") positiveCorrelation p(MGI:Syk, pmod(Ph)) View Subject | View Object

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Evidence aadaa2f3eb
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Most importantly, pathological tau species clearly colo- calize with pSyk (Y525/526) in hippocampal neurons (Fig. 4b).

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

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Cell Ontology (CL)
hippocampal neuron

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

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Annotations
Cell Ontology (CL)
hippocampal neuron

Evidence 643fd7f81e
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We observed a colocalization between pSyk and pTau (S202) immuno- reactivities in cortical neurons.

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

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Annotations
Cell Ontology (CL)
cerebral cortex neuron

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

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Annotations
Cell Ontology (CL)
cerebral cortex neuron

Evidence 6ee3d286be
JSON

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).

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

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MeSH
Neurons

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

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Annotations
MeSH
Neurons

Evidence 3fd0216767
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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).

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

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MeSH
Hippocampus

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

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Annotations
MeSH
Hippocampus

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

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Annotations
MeSH
Hippocampus

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

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Annotations
MeSH
Hippocampus

Evidence d5c97d3b54
JSON

In addition, we observed that pSyk immunoreactivity is upregulated near A β plaques but neither colocalizes with microglia nor astrocytes suggesting that it could be of neuronal origin. (Fig. 1e).

a(HBP:"amyloid-beta aggregates") positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

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MeSH
Brain
MeSH
Alzheimer Disease

act(p(HGNC:SYK)) positiveCorrelation a(HBP:"amyloid-beta aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence 4b6190702e
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In conclusion, activated Syk is not only found in microglia but also in neurons near A β deposits, par- ticularly in dystrophic neurites of Tg APPsw and Tg PS1/APPsw mice supporting a possible role of Syk activation in the formation of dystrophic neurites.

a(HBP:"amyloid-beta aggregates") positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

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MeSH
Neurites
MeSH
Neurons

act(p(HGNC:SYK)) positiveCorrelation a(HBP:"amyloid-beta aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Neurons

Evidence ebbda9b0b8
JSON

We found an increase in Syk activation in DNs surrounding A β deposits as well as in neurons displaying an accumu- lation of phosphorylated Tau at Y18 and elevated levels of MC1 pathogenic tau conformers in AD brain sections whereas only weak immunoreactivity for pSyk was ob- served in brain sections from a non-demented control (Figs. 15, 16 and 17).

a(HBP:"amyloid-beta aggregates") positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:misfolded)) positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Tyr, 18)) positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Brain
MeSH
Alzheimer Disease

act(p(HGNC:SYK)) positiveCorrelation a(HBP:"amyloid-beta aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Brain
MeSH
Alzheimer Disease

act(p(HGNC:SYK)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Brain
MeSH
Alzheimer Disease

act(p(HGNC:SYK)) positiveCorrelation p(HGNC:MAPT, pmod(HBP:misfolded)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurites
MeSH
Brain
MeSH
Alzheimer Disease

Evidence 5f32a12c1e
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To investigate whether pathological Syk activation oc- curs in the brain of AD mouse models, we analyzed the brains of 116-week-old wild-type, Tg APPsw and Tg PS1/APPsw mice using high-resolution confocal micros- copy and immunofluorescence. All transgenic mice (Fig. 1b-e) exhibit an increased Iba-1 and GFAP reactiv- ity compared to wild-type littermates (Fig. 1a). Moreo- ver,wild-type some of the activated amoeboid microglia that are observed in transgenic mice are also strongly positive for pSyk (Fig. 1b-d).

bp(GO:"microglial cell activation") positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

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MeSH
Brain
MeSH
Alzheimer Disease

act(p(HGNC:SYK)) positiveCorrelation bp(GO:"microglial cell activation") View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases bp(GO:"microglial cell activation") View Subject | View Object

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MeSH
Brain
MeSH
Alzheimer Disease

Evidence 2347024e58
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In contrast, microscopic fields of older Tg APPsw mice containing A β deposits exhibit a strong increase in pSyk burden (799.95 ± 130.19%) com- pared to age-matched WT mice.

bp(GO:aging) increases p(HGNC:SYK) View Subject | View Object

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MeSH
Alzheimer Disease

Evidence 1fcb40ce43
JSON

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

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

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Cell Ontology (CL)
cerebral cortex neuron

bp(GO:aging) increases p(HGNC:SYK) View Subject | View Object

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Annotations
Cell Ontology (CL)
cerebral cortex neuron

Evidence 74eb6fae5f
JSON

We found that tau phosphorylation at Y18 is significantly increased in neurons that are also immunopositive for pSyk (Fig. 10d, p < 0.05) which is consistent with previous data showing that in vitro Syk can phosphorylates tau at Y18.

p(HGNC:MAPT, pmod(Ph, Tyr, 18)) positiveCorrelation p(HGNC:SYK) View Subject | View Object

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Annotations
MeSH
Neurons

p(HGNC:SYK) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

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Annotations
MeSH
Neurons

act(p(HGNC:SYK), ma(kin)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

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Evidence e19979f543
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Altogether, these data suggest that only certain pathogenic forms of tau (MC1, Y18) promote Syk activation, whereas Syk activation appears to directly in- duce tau phosphorylation at Y18 and to indirectly regulate tau phosphorylation at multiple epitopes (S396/404, S202) as well as tau misfolding (MC1, TOC1).

p(HGNC:MAPT, pmod(Ph, Tyr, 18)) increases act(p(HGNC:SYK)) View Subject | View Object

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act(p(HGNC:SYK)) directlyIncreases p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

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act(p(HGNC:SYK)) increases p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

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act(p(HGNC:SYK)) increases p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

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act(p(HGNC:SYK)) increases p(HGNC:MAPT, pmod(HBP:misfolded)) View Subject | View Object

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Evidence 6bdd2f3936
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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).

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

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Annotations
Cell Ontology (CL)
hippocampal neuron

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

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

Evidence b5ce7da44c
JSON

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

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

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

Evidence 37a8b01434
JSON

Dystrophic neurites are characterized by an accumula- tion of BACE-1 and sAPP β [31] and our previous work [28] has shown that Syk regulates BACE-1 expression and sAPP β levels suggesting that Syk upregulation in dystrophic neurites could contribute to the accumulation of BACE-1 and sAPP β .

p(HGNC:SYK) regulates p(HGNC:BACE1) View Subject | View Object

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MeSH
Neurites
MeSH
Neurons

p(HGNC:SYK) regulates p(HBP:"sAPP-beta") View Subject | View Object

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Annotations
MeSH
Neurites
MeSH
Neurons

Evidence cfc92ec8f8
JSON

Interestingly, Syk up- regulation in SH-SY5Y cells leads to a significant in- crease (1.7-fold) in phosphorylated tau at Y18 (Fig. 14c, p < 0.01) and at S396/404 (Fig. 14d, 3-fold, p < 0.0001) compared to control cells.

p(HGNC:SYK) increases p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

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p(HGNC:SYK) increases p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

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Evidence e5508f316a
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We have previously shown that Syk positively regulates GSK-3 β activity in vitro.

p(HGNC:SYK) increases act(p(HGNC:GSK3B)) View Subject | View Object

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Evidence 90c03402db
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Total tau levels are also sig- nificantly increased following Syk overexpression (Fig. 14e, 4.2-fold, p < 0.0001).

p(HGNC:SYK) increases p(HGNC:MAPT) View Subject | View Object

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Evidence 558869e97d
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We analyzed the possible impact of Syk overexpression on Tau mRNA levels by quantitative RT-PCR and found that Syk overexpression does not affect Tau transcription (data not shown) sug- gesting that Syk may regulate tau degradation or tau protein translation.

p(HGNC:SYK) causesNoChange r(HGNC:MAPT) View Subject | View Object

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