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PMID:22820466

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Citation

Um, JW, Nygaard, HB, Heiss, JK, Kostylev, MA, Stagi, M, Vortmeyer, A, Wisniewski, T, Gunther, EC and Strittmatter, SM (2012) Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15:1227-35

Abstract

Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Aβ-PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Aβ engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.

Links

PubMed PMC3431439 Online version:10.1038/nn.3178

Keywords

Alzheimer Disease/metabolism; Alzheimer Disease/physiopathology; Amyloid beta-Peptides/metabolism; Amyloid beta-Peptides/pharmacology; Animals; Blotting, Western; Calcium Signaling/physiology; Cell Line; Dendritic Spines/metabolism; Electroencephalography; Enzyme Activation; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurons/physiology; Phosphorylation; PrPC Proteins/genetics; PrPC Proteins/metabolism; Protein Binding; Proto-Oncogene Proteins c-fyn/physiology; Rats; Receptors, N-Methyl-D-Aspartate/metabolism; Receptors, N-Methyl-D-Aspartate/physiology; Seizures/genetics; Seizures/prevention & control; Synapses/drug effects; Synapses/metabolism; Synapses/physiology

Significance

Annotations

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

HUMAN:PRIO

located_in

GO:0014069: postsynaptic density

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PRIO

enables

GO:0001540: amyloid-beta binding

ECO:0000353: physical interaction evidence used in manual assertion

CHEBI:64647

F

Seeded From UniProt

complete

HUMAN:PRIO

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_input:(UniProtKB:P39688)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_input:(UniProtKB:P39688)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_input:(UniProtKB:Q01097)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:0090314: positive regulation of protein targeting to membrane

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1904645: response to amyloid-beta

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1900449: regulation of glutamate receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

RAT:PRIO

located_in

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_input:(UniProtKB:Q01097)

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:0090314: positive regulation of protein targeting to membrane

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1904645: response to amyloid-beta

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1900449: regulation of glutamate receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

RAT:FYN

located_in

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1902951: negative regulation of dendritic spine maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925,UniProtKB:Q01097

P

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1901216: positive regulation of neuron death

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925,UniProtKB:Q01097

P

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1905664: regulation of calcium ion import across plasma membrane

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1904645: response to amyloid-beta

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_regulation_target:(UniProtKB:Q01097)

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:0090314: positive regulation of protein targeting to membrane

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_regulation_target:(UniProtKB:Q01097)
  • regulates:(GO:0098703)

Seeded From UniProt

complete

MOUSE:FYN

involved_in

GO:1900449: regulation of glutamate receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:NMDE2

involved_in

GO:1901216: positive regulation of neuron death

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925,UniProtKB:P39688

P

Seeded From UniProt

complete

MOUSE:NMDE2

involved_in

GO:1902951: negative regulation of dendritic spine maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P04925,UniProtKB:P39688

P

Seeded From UniProt

complete

HUMAN:PRIO

enables

GO:0001540: amyloid-beta binding

ECO:0000353: physical interaction evidence used in manual assertion

CHEBI:64647

F

positively_regulates:(GO:0018108)

Seeded From UniProt

complete

HUMAN:PRIO

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_regulation_target:(UniProtKB:P39688)

Seeded From UniProt

complete

HUMAN:PRIO

part_of

GO:0014069: postsynaptic density

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_regulation_target:(UniProtKB:Q01097)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1900449: regulation of glutamate receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1902951: negative regulation of dendritic spine maintenance

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688,UniProtKB:Q01097

P

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1901216: positive regulation of neuron death

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688,UniProtKB:Q01097

P

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1905664: regulation of calcium ion import across plasma membrane

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:0090314: positive regulation of protein targeting to membrane

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_regulation_target:(UniProtKB:Q01097)
  • regulates:(GO:0098703)

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:1904645: response to amyloid-beta

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P39688

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:PRIO

enables

GO:0001540: amyloid-beta binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PRIO

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002609)
  • part_of:(GO:1904645)
  • has_regulation_target:(UniProtKB:P39688)

Seeded From UniProt

complete

Notes

See also

References

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