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

Authors

Iryna Leshchyns'Ka, University of New South Wales
Heng Tai Liew, University of New South Wales
Claire E. Shepherd, Neuroscience Research Australia
Glenda M. Halliday, Neuroscience Research Australia
Claire H. Stevens, University of New South WalesFollow
Yazi D. Ke, University of New South Wales
Lars M. Ittner, University of New South Wales
Vladimir Sytnyk, University of New South Wales

RIS ID

107476

Publication Details

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.

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.