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

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  • Iryna Leshchyns’ka

    (School of Biotechnology and Biomolecular Sciences, University of New South Wales)

  • Heng Tai Liew

    (School of Biotechnology and Biomolecular Sciences, University of New South Wales)

  • Claire Shepherd

    (Neuroscience Research Australia)

  • Glenda M. Halliday

    (Neuroscience Research Australia)

  • Claire H. Stevens

    (Neuroscience Research Australia
    Dementia Research Unit, School of Medical Sciences, The University of New South Wales)

  • Yazi D. Ke

    (Dementia Research Unit, School of Medical Sciences, The University of New South Wales)

  • Lars M. Ittner

    (Neuroscience Research Australia
    Dementia Research Unit, School of Medical Sciences, The University of New South Wales)

  • Vladimir Sytnyk

    (School of Biotechnology and Biomolecular Sciences, University of New South Wales)

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.

Suggested Citation

  • Iryna Leshchyns’ka & Heng Tai Liew & Claire Shepherd & Glenda M. Halliday & Claire H. Stevens & Yazi D. Ke & Lars M. Ittner & Vladimir Sytnyk, 2015. "Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease," Nature Communications, Nature, vol. 6(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9836
    DOI: 10.1038/ncomms9836
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