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PubMed: 25331948

Title
The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation.
Journal
The Journal of biological chemistry
Volume
289
Issue
None
Pages
33927-44
Date
2014-12-05
Authors
Ait-Ghezala G | Bachmeier C | Beaulieu-Abdelahad D | Crawford F | Jin C | Laco G | Lin Y | Mullan M | Paris D

Evidence d3dcb38fe3
JSON

We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes.

a(CHEBI:"amyloid-beta") positiveCorrelation p(MGI:Syk) View Subject | View Object

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act(p(HGNC:GSK3B), ma(kin)) increases a(HBP:"Tau epitope, PHF1") View Subject | View Object

Appears in Networks:

p(MGI:Mapt, pmod(Ph, Ser, 202)) positiveCorrelation p(MGI:Syk) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

p(MGI:Syk) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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p(MGI:Syk) positiveCorrelation p(MGI:Mapt, pmod(Ph, Ser, 202)) View Subject | View Object

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Evidence ee09e8e42c
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We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB).

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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a(CHEBI:Nilvadipine) directlyDecreases complex(GO:"L-type voltage-gated calcium channel complex") View Subject | View Object

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Evidence 2a33d565fa
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Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes

a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 199)) View Subject | View Object

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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Evidence a56321a6ce
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We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition.

a(HBP:"BAY61-3606") directlyDecreases act(p(HGNC:SYK)) View Subject | View Object

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act(p(HGNC:GSK3B), ma(kin)) positiveCorrelation act(p(HGNC:SYK)) View Subject | View Object

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p(HGNC:GSK3B, pmod(Ph, Ser, 9)) negativeCorrelation act(p(HGNC:SYK)) View Subject | View Object

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act(p(HGNC:SYK)) negativeCorrelation p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

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act(p(HGNC:SYK)) positiveCorrelation act(p(HGNC:GSK3B), ma(kin)) View Subject | View Object

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Evidence 22383304f5
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The Syk inhibitor BAY61-3606 was used as a positive control in the Syk activity assay, and a dose-dependent inhibition of Syk activity was observed with BAY61-3606 as expected (Fig. 5B).

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases act(p(HGNC:SYK)) View Subject | View Object

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Evidence 6ce59e68b8
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We found that, like (-)-nilvadipine, Syk inhibition with the selective Syk inhibitor BAY61-3606 resulted in decreased sAPPβ secretion, BACE-1 mRNA, and BACE-1 protein expression (data not shown).

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases act(p(HGNC:SYK)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases sec(p(HBP:"sAPP-beta")) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases r(HGNC:BACE1) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(HGNC:BACE1) View Subject | View Object

Appears in Networks:

a(CHEBI:Nilvadipine) decreases sec(p(HBP:"sAPP-beta")) View Subject | View Object

Appears in Networks:

a(CHEBI:Nilvadipine) decreases r(HGNC:BACE1) View Subject | View Object

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a(CHEBI:Nilvadipine) decreases p(HGNC:BACE1) View Subject | View Object

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act(p(HGNC:SYK)) increases sec(p(HBP:"sAPP-beta")) View Subject | View Object

Appears in Networks:

act(p(HGNC:SYK)) increases r(HGNC:BACE1) View Subject | View Object

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act(p(HGNC:SYK)) increases p(HGNC:BACE1) View Subject | View Object

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Evidence dc39d4035e
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In addition, we verified that pharmacological inhibition of Syk with BAY61-3606 resulted in a blockade of NFkB activation and that genetic down-regulation of SYK using shRNA also prevented NFkB activation (data not shown) thus highlighting Syk as a key player of NFkB activation.

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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p(HGNC:SYK) increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Evidence 99ab68d672
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We found that Syk inhibition with the selective Syk inhibitor BAY61-3606 suppresses Aβ production in 7W CHO cells overexpressing APP (Fig. 6A).

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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p(HGNC:SYK) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence afc04147ac
JSON

We show that the selective Syk inhibitor BAY61-3606 stimulates the transport of Aβ across the BBB in vitro mimicking the biological activity of (-)-nilvadipine in this model (Fig. 7A).

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

act(p(HGNC:SYK)) decreases tloc(a(CHEBI:"amyloid-beta"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

Evidence 52113777fe
JSON

We observed that BAY61-3606 significantly reduces brain Aβ38, Aβ40, and Aβ42 levels in Tg PS1/ APPsw mice (Fig. 7, C and D).

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(MGI:App, frag("1_38")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 97ce51b0c3
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In addition, we found that BAY61-3606 stimulates the clearance of Aβ across the BBB in wild-type mice as demonstrated by increased circulating plasma levels of human Aβ42 in mice treated with the Syk inhibitor compared with vehicle-treated mice following the intracranial injection of human Aβ42 (Fig. 7B)

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") increases tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

Evidence de86675a7f
JSON

We observed a reduction in Tau phosphorylation at the Tyr-18 epitope as expected (Fig. 8) in BAY61-3606-treated mice.

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(MGI:Mapt, pmod(Ph, Tyr, 18)) View Subject | View Object

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Evidence ba37d4c3df
JSON

Interestingly, we also detected a reduction in Tau phosphorylation at PHF-1 (Ser(P)- 396/Ser(P)-404) and CP13 (Ser(P)-202) in epitopes following treatment of Tg Tau P301S mice with BAY61-3606, whereas the RZ3 (Thr(P)-231) Tau epitope was not significantly impacted (Fig. 8) suggesting that Syk inhibition may also control the activity of other downstream kinases involved in Tau hyperphosphorylation

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(MGI:Mapt, pmod(Ph, Ser, 396)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(MGI:Mapt, pmod(Ph, Ser, 404)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(MGI:Mapt, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") causesNoChange p(MGI:Mapt, pmod(Ph, Tyr, 231)) View Subject | View Object

Appears in Networks:

Evidence 76f642c626
JSON

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9,Aand B) suggesting that blocking Syk activity results in GSK3β inhibition.

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") increases p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

p(HGNC:GSK3B, pmod(Ph, Ser, 9)) decreases act(p(HGNC:GSK3B)) View Subject | View Object

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Evidence ce6d7cb6eb
JSON

We found that KT5270 effectively suppressed GSK3β phosphorylation at Ser-9 induced by BAY61-3606 (Fig. 10B) suggesting that this event is mediated by an activation of PKA.

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") increases p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

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p(FPLX:PKA) increases p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

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Evidence fe78c27f04
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We further confirmed that possibility by showing that Tau phosphorylation at the typical GSK3β sites (PHF-1 and CP13) is reduced following treatment of SH-SY5Y cells with BAY61-3606, whereas Tau phosphorylation at the RZ3 site was not significantly impacted in SH-SY5Y cells (Fig. 9C).

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") causesNoChange p(HGNC:MAPT, pmod(Ph, Tyr, 231)) View Subject | View Object

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p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

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p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

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Evidence 377b0d4b15
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We found that treatment of SH-SY5Y cells with BAY61-3606 inhibits AKT phosphorylation (Fig. 9, A and B), which is consistent with previous studies (59) investigating the impact of Syk inhibition on AKT activation.

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases p(FPLX:AKT, pmod(Ph, Ser, 473)) View Subject | View Object

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Evidence c938273ef1
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We found that Syk inhibition with BAY61-3606 induced CREB phosphorylation, although that event is inhibited in the presence of a selective PKA inhibitor (Fig. 10, A and B) further showing that Syk inhibition results in PKA activation.

a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") increases p(HGNC:CREB1, pmod(Ph)) View Subject | View Object

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p(HGNC:SYK) decreases act(p(FPLX:PKA)) View Subject | View Object

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act(p(FPLX:PKA)) increases p(HGNC:CREB1, pmod(Ph)) View Subject | View Object

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Evidence dcd905823a
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PMA is a known agonist of PKC, which leads to the activation of the PKC/RAS/RAF/MEK/MAPK pathway that ultimately induces NFkB activation (46–48)

a(CHEBI:"phorbol 13-acetate 12-myristate") increases act(p(FPLX:PKC)) View Subject | View Object

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a(CHEBI:"phorbol 13-acetate 12-myristate") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Evidence 83dbd7289f
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In particular, we monitored RAF phosphorylation following treatment with (-)-nilvadipine and observed that (-)-nilvadipine prevents RAF phosphorylation induced by PMA (Fig. 4, C and D) suggesting that (-)-nilvadipine is impacting a target upstream of RAF

a(CHEBI:Nilvadipine) decreases p(HGNC:RAF1, pmod(Ph)) View Subject | View Object

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a(CHEBI:"phorbol 13-acetate 12-myristate") increases p(HGNC:RAF1, pmod(Ph)) View Subject | View Object

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Evidence d9b65f1076
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As expected, RAF phosphorylation induced by PMA as well as basal RAF phosphorylation were reduced in 7W CHO cells transfected with SYK shRNA confirming a reduction in Syk activity (Fig. 6B).

a(CHEBI:"phorbol 13-acetate 12-myristate") increases p(HGNC:RAF1, pmod(Ph)) View Subject | View Object

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act(p(HGNC:SYK)) increases p(HGNC:RAF1, pmod(Ph)) View Subject | View Object

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Evidence 8d96aebed0
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Tyrosine kinases, including Syk and Bruton’s tyrosine kinase (BTK), are activated following PMA treatment (49, 50), act upstream of RAS/RAF (51, 52), and mediate the activation of the NFkB pathway (53).

a(CHEBI:"phorbol 13-acetate 12-myristate") increases act(p(HGNC:SYK)) View Subject | View Object

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a(CHEBI:"phorbol 13-acetate 12-myristate") increases act(p(HGNC:BTK)) View Subject | View Object

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act(p(HGNC:SYK)) regulates act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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act(p(HGNC:BTK)) regulates act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Evidence 6327d8df51
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Following 24 h of treatment with the pure enantiomers or the racemic mixture of nilvadipine, a dose-dependent inhibition of Aβ production was observed (Fig. 1A).

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 456ee57813
JSON

In addition, a reduction in BACE-1 protein levels was observed following treatment of HEK293 cells with (-)-nilvadipine or racemic nilvadipine (Fig. 1D) further suggesting that the inhibition of Aβ production observed following nilvadipine treatment is mediated in part by a reduction of BACE-1 expression.

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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a(CHEBI:Nilvadipine) decreases p(HGNC:BACE1) View Subject | View Object

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p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 3d34806cfd
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We tested the effect of an acute treatment with (-)-nilvadipine or (+)-nilvadipine on brain Aβ levels using Tg PS1/APPsw mice, and we observed that both (-)-nilvadipine and (+)-nilvadipine acutely reduced brain Aβ levels with similar potency (Fig. 2, C and D).

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
MeSH
Brain

Evidence e03ddae8a7
JSON

We have previously shown that racemic nilvadipine affects the β-cleavage of APP and reduces sAPPβ secretion

a(CHEBI:Nilvadipine) decreases act(p(HGNC:APP)) View Subject | View Object

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a(CHEBI:Nilvadipine) decreases sec(p(HBP:"sAPP-beta")) View Subject | View Object

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Evidence 2a433b0fe0
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We found that both (-)-nilvadipine and racemic nilvadipine reduce BACE-1 mRNA expression (Fig. 1C) induced by TNFα

a(CHEBI:Nilvadipine) decreases r(HGNC:BACE1) View Subject | View Object

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p(HGNC:TNF) increases p(HGNC:BACE1) View Subject | View Object

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Evidence ecfc55920c
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As (-)-nilvadipine and racemic nilvadipine inhibit BACE-1 transcription, we evaluated whether (-)-nilvadipine was impacting NFkB activation because NFkB has been shown to play an important role in the regulation of BACE-1 transcription and expression (36, 37, 43, 44)

a(CHEBI:Nilvadipine) decreases p(HGNC:BACE1) View Subject | View Object

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complex(GO:"NF-kappaB complex") regulates p(HGNC:BACE1) View Subject | View Object

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Evidence cdb741cc3c
JSON

We found that both the (-)- and (+)-nilvadipine enantiomers enhance Aβ42 clearance from the brain to the peripheral side of the in vitro BBB model (Fig. 2A).

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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Annotations
MeSH
Brain

a(CHEBI:Nilvadipine) increases bp(GO:"amyloid-beta clearance by transcytosis") View Subject | View Object

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Annotations
MeSH
Brain

Evidence 201560b0c7
JSON

Data show that (-)-nilvadipine stimulated the clearance of human Aβ42 across the BBB as more human Aβ42 was detected in the plasma of (-)-nilvadipine-treated mice than control animals (Fig. 2B).

a(CHEBI:Nilvadipine) increases tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

Evidence 6946c86aad
JSON

Western blot analyses of brain homogenates show that (-)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes (Fig. 3).

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 199)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 396)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 404)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence c0a8ac6918
JSON

Using a cell-free assay using human recombinant Syk, we observed that (-)-nilvadipine dose-dependently inhibits Syk activity (Fig. 5A)

a(CHEBI:Nilvadipine) decreases act(p(HGNC:SYK)) View Subject | View Object

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Evidence 52ce084cd5
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To ensure that the reduction in Syk activity observed was not due to an interaction of the peptide substrate with (-)-nilvadipine, we also verified that (-)-nilvadipine was able to directly bind to Syk.

a(CHEBI:Nilvadipine) increases complex(a(CHEBI:Nilvadipine), p(HGNC:SYK)) View Subject | View Object

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Evidence 82f703a00b
JSON

We measured the binding affinity of (-)-nilvadipine for Syk using biolayer interferometry and confirmed that (-)-nilvadipine binds to human recombinant Syk with a binding dissociation constant (KD) of 2.1 µM (Fig. 5C), further suggesting that Syk is the possible target impacted by nilvadipine.

a(CHEBI:Nilvadipine) increases complex(a(CHEBI:Nilvadipine), p(HGNC:SYK)) View Subject | View Object

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Evidence 870a7c43f0
JSON

The magnitude of the NFkB inhibition following (-)-nilvadipine treatment was also reduced in clones of HEK293 NFkB luciferase reporter cells in which Syk expression had been silenced (data not shown) further suggesting that Syk is required to mediate the inhibition of NFkB activity induced by (-)-nilvadipine.

a(CHEBI:Nilvadipine) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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p(HGNC:SYK) regulates act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Evidence 116e8c2122
JSON

Wetested a selective BTK inhibitor (BTK inhibitor III, 1-(3-(4-amino-3-(4-phenyloxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, N-acryloyl-(3-(4-amino-3-(4-phenyloxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine) on Aβ production, and we found that this compound was unable to significantly inhibit Aβ production (data not shown) suggesting that the Aβ-lowering properties of nilvadipine are not mediated via an inhibition of BTK.

a(PUBCHEM:71656932) decreases act(p(HGNC:BTK)) View Subject | View Object

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a(PUBCHEM:71656932) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence a8cdf365a1
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Interestingly, Aβ production in 7W CHO cells transfected with SYK shRNA compared with 7W CHO cells (Fig. 6C) was significantly reduced, further demonstrating the involvement of Syk in the regulation of Aβ production.

act(p(HGNC:SYK)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 618e2d177e
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Syk has been shown to mediate the phosphorylation of Tau at Tyr-18 (56).

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

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Evidence 092f209819
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PKA is a known substrate of Syk, and it has been shown that Syk inhibits PKA activity by phosphorylating Tyr-330 of the PKA catalytic subunit (60), further supporting our observation.

p(HGNC:SYK) decreases act(p(FPLX:PKA)) View Subject | View Object

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p(HGNC:SYK) increases p(FPLX:PKA, pmod(Ph, Tyr, 330)) View Subject | View Object

Appears in Networks:

p(FPLX:PKA, pmod(Ph, Tyr, 330)) decreases act(p(FPLX:PKA)) View Subject | View Object

Appears in Networks:

Evidence acdf300d00
JSON

Weobserved that (-)-nilvadipine inhibits NFkB activation in response to TNFα (Fig. 4A) or phorbol 12-myristate 13-acetate (PMA) (Fig. 4B) by using an NFkB-luciferase reporter cell line to monitor NFkB activation, thus suggesting a possible mechanism responsible for the inhibition of BACE-1 transcription following nilvadipine treatment

composite(a(CHEBI:"phorbol 13-acetate 12-myristate"), a(CHEBI:Nilvadipine)) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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composite(a(CHEBI:Nilvadipine), p(HGNC:TNF)) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Evidence 3ccbf2773a
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Tumor necrosis factor-α (TNFα) has been shown to induce BACE-1 expression and to contribute to brain accumulation of Aβ peptides

p(HGNC:TNF) increases p(HGNC:BACE1) View Subject | View Object

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p(HGNC:TNF) increases a(MESH:"Amyloid beta-Peptides") View Subject | View Object

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Annotations
MeSH
Brain

Evidence 8c1ac74b1a
JSON

For instance, the small GTPase Rho and its downstream effector Rho-associated coiled-coil containing protein kinase (ROCK) have been shown to contribute to TNFα induction of NFkB activation (45).

p(HGNC:TNF) increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Appears in Networks:

composite(p(FPLX:RHO), p(HGNC:ROCK1)) increases act(p(HGNC:TNF)) View Subject | View Object

Appears in Networks:

composite(p(FPLX:RHO), p(HGNC:ROCK1)) increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Appears in Networks:

Evidence ac1a2761e5
JSON

GSK3β phosphorylation at Ser-9 has been shown to be mediated by PKA and AKT (protein kinase B) (57, 58).

p(FPLX:AKT) regulates p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

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p(FPLX:PKA) regulates p(HGNC:GSK3B, pmod(Ph, Ser, 9)) View Subject | View Object

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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.