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PMID:21857966

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Citation

Li, B, Zhong, L, Yang, X, Andersson, T, Huang, M and Tang, SJ (2011) WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity. PLoS ONE 6:e22920

Abstract

Neurodegenration is a pathological hallmark of Alzheimer's disease (AD), but the underlying molecular mechanism remains elusive. Here, we present evidence that reveals a crucial role of Wnt5a signaling in this process. We showed that Wnt5a and its receptor Frizzled-5 (Fz5) were up-regulated in the AD mouse brain, and that beta-amyloid peptide (Aβ), a major constituent of amyloid plaques, stimulated Wnt5a and Fz5 expression in primary cortical cultures; these observations indicate that Wnt5a signaling could be aberrantly activated during AD pathogenesis. In support of such a possibility, we observed that inhibition of Wnt5a signaling attenuated while activation of Wnt5a signaling enhanced Aβ-evoked neurotoxicity, suggesting a role of Wnt5a signaling in AD-related neurodegeneration. Furthermore, we also demonstrated that Aβ-induced neurotoxicity depends on inflammatory processes, and that activation of Wnt5a signaling elicited the expression of proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a signaling attenuated the Aβ-induced expression of the cytokines in cortical cultures. Our findings collectively suggest that aberrantly up-regulated Wnt5a signaling is a crucial pathological step that contributes to AD-related neurodegeneration by regulating neuroinflammation.

Links

PubMed PMC3157339 Online version:10.1371/journal.pone.0022920

Keywords

Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Amyloid beta-Peptides/genetics; Amyloid beta-Peptides/metabolism; Amyloid beta-Peptides/pharmacology; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism; Animals; Blotting, Western; Cell Survival/drug effects; Cells, Cultured; Hippocampus/metabolism; Hippocampus/pathology; Humans; Hydrogen Peroxide/pharmacology; Immunohistochemistry; Interleukin-1beta/metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons/drug effects; Neurons/metabolism; Neurotoxicity Syndromes/genetics; Neurotoxicity Syndromes/metabolism; Oxidants/pharmacology; Peptide Fragments/genetics; Peptide Fragments/metabolism; Peptide Fragments/pharmacology; Recombinant Proteins/metabolism; Recombinant Proteins/pharmacology; Signal Transduction/drug effects; Tumor Necrosis Factor-alpha/metabolism; Wnt Proteins/genetics; Wnt Proteins/metabolism; Wnt Proteins/pharmacology; Wnt-5a Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:A4

involved_in

GO:0010468: regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P49768

P

  • regulates_expression_of:(UniProtKB:Q13467)
  • regulates:(GO:0018108)
  • occurs_in:(UBERON:0002421)
  • regulates_o_occurs_in:(UBERON:0002421)|regulates_expression_of(UniProtKB:P41221)
  • regulates:(GO:0018108)
  • occurs_in:(UBERON:0002421)
  • regulates_o_occurs_in:(UBERON:0002421)

Seeded From UniProt

complete

HUMAN:A4

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P49768

P

  • has_input:(UniProtKB:Q9UQM7)

Seeded From UniProt

complete

MOUSE:IL10

involved_in

GO:1903208: negative regulation of hydrogen peroxide-induced neuron death

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134

P

  • regulates_o_occurs_in:(CL:0002609)
  • part_of:(GO:0050728)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0002609)
  • has_input:(UniProtKB:P06804)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:Q9EQD0

P

  • regulates_o_occurs_in:(CL:0002609)
  • has_input:(UniProtKB:P06804)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0032731: positive regulation of interleukin-1 beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0032731: positive regulation of interleukin-1 beta production

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:Q9EQD0

P

  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_expression_of:(UniProtKB:Q9Z1E3)
  • regulates_o_occurs_in:(CL:0002609)|regulates_expression_of(UniProtKB:Q9WUL6)
  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0043122: regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:1901216: positive regulation of neuron death

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:FZD5

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:P22725

P

  • regulates_o_occurs_in:(CL:0002609)
  • has_input:(UniProtKB:P06804)

Seeded From UniProt

complete

MOUSE:FZD5

involved_in

GO:0032731: positive regulation of interleukin-1 beta production

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:P22725

P

  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:WNT5A

involved_in

GO:0050727: regulation of inflammatory response

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:A4

involved_in

GO:0030111: regulation of Wnt signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0010468

P

  • occurs_in:(UBERON:0002421)
  • regulates_o_occurs_in:(UBERON:0002421)
  • causally_upstream_of:(GO:0070997)

Seeded From UniProt

complete

HUMAN:A4

involved_in

GO:0010468: regulation of gene expression

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P49768

P

  • regulates_expression_of:(ENSEMBL:ENSG00000163251)
  • regulates:(GO:0018108)
  • occurs_in:(UBERON:0002421)
  • regulates_o_occurs_in:(UBERON:0002421)|regulates_expression_of(ENSEMBL:ENSG00000114251)
  • regulates:(GO:0018108)
  • occurs_in:(UBERON:0002421)
  • regulates_o_occurs_in:(UBERON:0002421)

Seeded From UniProt

complete

HUMAN:A4

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P49768

P

has_regulation_target:(UniProtKB:Q9UQM7)

Seeded From UniProt

complete

HUMAN:IL10

involved_in

GO:0050728: negative regulation of inflammatory response

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0050718: positive regulation of interleukin-1 beta secretion

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:Q9EQD0

P

regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:1904469: positive regulation of tumor necrosis factor secretion

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:Q9EQD0

P

  • regulates_o_occurs_in:(CL:0002609)
  • has_regulation_target:(UniProtKB:P06804)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:1901216: positive regulation of neuron death

ECO:0000314: direct assay evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_expression_of:(ENSEMBL:ENSMUSG00000021025)
  • regulates_o_occurs_in:(CL:0002609)|regulates_expression_of(ENSEMBL:ENSMUSG00000020941)
  • regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0043122: regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0050718: positive regulation of interleukin-1 beta secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:1904469: positive regulation of tumor necrosis factor secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0002609)
  • has_regulation_target:(UniProtKB:P06804)

Seeded From UniProt

complete

MOUSE:FZD5

involved_in

GO:0050718: positive regulation of interleukin-1 beta secretion

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:P22725

P

regulates_o_occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:FZD5

involved_in

GO:1904469: positive regulation of tumor necrosis factor secretion

ECO:0000316: genetic interaction evidence used in manual assertion

ComplexPortal:CPX-1134,UniProtKB:P22725

P

  • regulates_o_occurs_in:(CL:0002609)
  • has_regulation_target:(UniProtKB:P06804)

Seeded From UniProt

complete

Notes

See also

References

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