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Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease

Journal Article


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Abstract


  • Alzheimer’s disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippocampus. This enrichment is abolished in the hippocampus of AD patients and in brains of mice overexpressing the human amyloid-β (Aβ) precursor protein carrying the pathogenic Swedish mutation. Aβ binds to NCAM2 at the cell surface of cultured hippocampal neurons and induces removal of NCAM2 from synapses. In AD hippocampus, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippocampal neurons. Aβ-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Aβ-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss.

Authors


  •   Leshchyns'Ka, Iryna (external author)
  •   Liew, Heng Tai (external author)
  •   Shepherd, Claire E. (external author)
  •   Halliday, Glenda M. (external author)
  •   Stevens, Claire H.
  •   Ke, Yazi D. (external author)
  •   Ittner, Lars M. (external author)
  •   Sytnyk, Vladimir (external author)

Publication Date


  • 2015

Citation


  • Leshchyns'Ka, I., Liew, H., Shepherd, C. E., Halliday, G. M., Stevens, C. H., Ke, Y. D., Ittner, L. M. & Sytnyk, V. (2015). Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. Nature Communications, 6 (November), 8836-1-8836-18.

Scopus Eid


  • 2-s2.0-84948689255

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4832&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3809

Has Global Citation Frequency


Start Page


  • 8836-1

End Page


  • 8836-18

Volume


  • 6

Issue


  • November

Place Of Publication


  • United Kingdom

Abstract


  • Alzheimer’s disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippocampus. This enrichment is abolished in the hippocampus of AD patients and in brains of mice overexpressing the human amyloid-β (Aβ) precursor protein carrying the pathogenic Swedish mutation. Aβ binds to NCAM2 at the cell surface of cultured hippocampal neurons and induces removal of NCAM2 from synapses. In AD hippocampus, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippocampal neurons. Aβ-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Aβ-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss.

Authors


  •   Leshchyns'Ka, Iryna (external author)
  •   Liew, Heng Tai (external author)
  •   Shepherd, Claire E. (external author)
  •   Halliday, Glenda M. (external author)
  •   Stevens, Claire H.
  •   Ke, Yazi D. (external author)
  •   Ittner, Lars M. (external author)
  •   Sytnyk, Vladimir (external author)

Publication Date


  • 2015

Citation


  • Leshchyns'Ka, I., Liew, H., Shepherd, C. E., Halliday, G. M., Stevens, C. H., Ke, Y. D., Ittner, L. M. & Sytnyk, V. (2015). Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. Nature Communications, 6 (November), 8836-1-8836-18.

Scopus Eid


  • 2-s2.0-84948689255

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4832&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3809

Has Global Citation Frequency


Start Page


  • 8836-1

End Page


  • 8836-18

Volume


  • 6

Issue


  • November

Place Of Publication


  • United Kingdom