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  3. PubMed:30232325

PubMed: 30232325

Title
A role for APP in Wnt signalling links synapse loss with β-amyloid production.
Journal
Translational psychiatry
Volume
8
Issue
None
Pages
179
Date
2018-09-20
Authors
Elliott C | Killick R | Al-Shawi R | Baillie G | Ballard CG | Broadstock M | Cuadrado A | Morin P | Ribe E | Rojo AI | Semenov M | Simons P | Xia W

Evidence 8adf2b6168
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Aβ synaptoxicity is Dkk1-dependent12,24 and also appears to be APP-dependent25.

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

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Confidence
High

p(HGNC:APP) increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
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Confidence
High

p(HGNC:DKK1) increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
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Confidence
High

Evidence 83cb3c4285
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The Wnt-PCP signalling pathway acts through RhoA and ROCK26, and can be inhibited pharmacologically, for example, with fasudil24, a ROCK inhibitor that is in clinical use for the treatment of cerebral vasospasm.

a(CHEBI:"fasudil hydrochloride") decreases bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

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Confidence
High

Evidence 142e677389
JSON

Fasudil also reversed the stimulatory effect of Vangl2 and Dkk1 on Aβ production in the same cells as determined by ELISA based quantification of Aβ1–40 levels in the paired culture media from the same experiments (Fig. 3d).

a(CHEBI:"fasudil hydrochloride") decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

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Confidence
High

Evidence d3297e2895
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Animals receiving fasudil had significantly lower soluble Aβ1–40 levels than controls (Fig. 4b).

a(CHEBI:"fasudil hydrochloride") decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

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Confidence
High

Evidence 5f1248c262
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APP has previously been shown to interact with Vangl2, a Wnt-PCP-specific co-receptor protein, and independently has been shown to bind LRP6, a receptor component of the Wnt-β-catenin pathway21.

bp(GO:"Wnt signaling pathway, planar cell polarity pathway") association p(HGNC:VANGL2) View Subject | View Object

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Confidence
High

bp(GO:"canonical Wnt signaling pathway") association p(HGNC:LRP6) View Subject | View Object

Appears in Networks:
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Confidence
High

p(HGNC:LRP6) association bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:VANGL2) association bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 3d348c6097
JSON

In cells expressing either wild-type or Swedish APP, the amount of Aβ produced was reduced in cells stimulated with Wnt3a, which promotes Wnt-βcatenin signalling, whereas Aβ production was enhanced in cells stimulated with Wnt5a, which promotes Wnt-PCP signalling (Fig. 2c).

bp(GO:"Wnt signaling pathway, planar cell polarity pathway") increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Confidence
High

bp(GO:"canonical Wnt signaling pathway") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Confidence
High

act(p(HGNC:WNT3A)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Confidence
High

act(p(HGNC:WNT3A)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Confidence
High

Evidence 3ed98c255d
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Comparison of signalling activity and Aβ production under each of the different conditions showed clearly that Aβ production was negatively correlated with Wnt-β-catenin signalling activity (Fig. 2d) and positively correlated with Wnt-PCP signalling (Fig. 2e).

bp(GO:"Wnt signaling pathway, planar cell polarity pathway") positiveCorrelation bp(GO:"amyloid-beta formation") View Subject | View Object

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Confidence
High

bp(GO:"amyloid-beta formation") negativeCorrelation bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

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Confidence
High

bp(GO:"amyloid-beta formation") positiveCorrelation bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

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Confidence
High

bp(GO:"canonical Wnt signaling pathway") negativeCorrelation bp(GO:"amyloid-beta formation") View Subject | View Object

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Confidence
High

Evidence f7a8c9c0d1
JSON

APP did though potentiate both Wnt3a-driven Wnt-β-catenin signalling and Wnt5a-driven Wnt-PCP signalling.

p(HGNC:APP) increases act(p(HGNC:WNT5A)) View Subject | View Object

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Confidence
High

p(HGNC:APP) increases act(p(HGNC:WNT3A)) View Subject | View Object

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Confidence
High

act(p(HGNC:WNT3A)) increases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:WNT5A)) increases bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

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Annotations
Confidence
High

Evidence f7c8ede5f9
JSON

In contrast with wild-type APP which, as before, potentiated both canonical and non-canonical Wnt signalling, the Swedish mutant form of APP antagonised canonical Wnt signalling (Fig. 2a), and potentiated non-canonical Wnt signalling to a greater degree than wild-type APP (APPWT) (Fig. 2b).

p(HGNC:APP) increases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

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Confidence
High

p(HGNC:APP) increases bp(GO:"non-canonical Wnt signaling pathway") View Subject | View Object

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Confidence
High

p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) decreases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

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Confidence
High

p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) increases bp(GO:"non-canonical Wnt signaling pathway") View Subject | View Object

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Confidence
High

Evidence b2bf82f9b0
JSON

Overexpression of APP enhanced the inhibitory effects of Dkk1 on Wnt3a induced Wnt-β-catenin signalling, counteracting the enhanced activity resulting from APP overexpression and reducing the IC50 of Dkk1 to 122ng/mL from 173ng/mL in the absence of APP (Fig. 2f) .

p(HGNC:APP) increases act(p(HGNC:DKK1)) View Subject | View Object

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Confidence
Medium

act(p(HGNC:DKK1)) decreases act(p(HGNC:WNT3A)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

act(p(HGNC:DKK1)) decreases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

act(p(HGNC:WNT3A)) increases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 972ae84f40
JSON

In contrast, the stimulatory effects of Dkk1 on WntPCP signalling induced by Wnt5a were enhanced by APP overexpression, decreasing the EC50 of Dkk1 to 599ng/ mL from 1405ng/mL (Fig. 2g).

p(HGNC:APP) increases act(p(HGNC:DKK1)) View Subject | View Object

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Confidence
High

act(p(HGNC:DKK1)) increases act(p(HGNC:WNT5A)) View Subject | View Object

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Confidence
High

act(p(HGNC:DKK1)) increases bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 729400e97e
JSON

Dkk1 resulted in substantial loss of dendritic spines, which was blocked by 10µM fasudil treatment (Fig. 3e, f).

p(HGNC:DKK1) decreases a(MESH:"Dendritic Spines") View Subject | View Object

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Confidence
High

composite(a(CHEBI:"fasudil hydrochloride"), p(HGNC:DKK1)) causesNoChange a(MESH:"Dendritic Spines") View Subject | View Object

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Confidence
High

Evidence ce5605c9b6
JSON

Notably, in parallel with the protective effect of fasudil on synapses (Fig. 3e, f), treatment with fasudil reversed the stimulatory effects of Dkk1 on Aβ production (Fig. 3g).

composite(a(CHEBI:"fasudil hydrochloride"), p(HGNC:DKK1)) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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Confidence
Medium

p(HGNC:DKK1) increases bp(GO:"amyloid-beta formation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence eaeee0ef4c
JSON

In addition to causing a significant reduction in the numbers of dendritic spines, Dkk1 treatment also resulted a substantial increase in levels of all three Aβ species (Fig. 3g).

p(HGNC:DKK1) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:DKK1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 8f894baab4
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As previously reported, Dkk1-treatment markedly reduced the number of dendritic spines on APP+/+ neurons (Fig. 3a, b). In contrast, APP-deficiency protected neurons against the synaptotoxic activity of Dkk1 (Fig. 3a, b).

composite(p(HGNC:APP), p(HGNC:DKK1)) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence c937c6a5bf
JSON

The ability of APP to potentiate Wnt-β-catenin signalling in response to Wnt3a was enhanced by the overexpression of LRP6, and attenuated by Vangl2 (Fig. 1g).

composite(p(HGNC:APP), p(HGNC:LRP6)) increases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

composite(p(HGNC:APP), p(HGNC:VANGL2)) decreases bp(GO:"canonical Wnt signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 865099a30d
JSON

Conversely, the ability of APP to potentiate Wnt-PCP signalling in response to Wnt5a was enhanced by Vangl2 and attenuated by LRP6 (Fig. 1h).

composite(p(HGNC:APP), p(HGNC:LRP6)) decreases bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

composite(p(HGNC:APP), p(HGNC:VANGL2)) increases bp(GO:"Wnt signaling pathway, planar cell polarity pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 6cd8072765
JSON

Co-expression of LRP6 with APP reduced the production of Aβ, while co-expression of Vangl2 with APP led to increased Aβ production (Fig. 2c).

composite(p(HGNC:APP), p(HGNC:LRP6)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

composite(p(HGNC:APP), p(HGNC:VANGL2)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 9119cf9701
JSON

As expected, cells expressing the Swedish mutant form of APP695 produced much more Aβ than the control wildtype-expressing cells.

p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

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