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

作者：Leshchyns'ka Iryna; Liew Heng Tai; Shepherd Claire; Halliday Glenda M; Stevens Claire H; Ke Yazi D; Ittner Lars M; Sytnyk Vladimir^*

来源：Nature Communications, 2015, 6(1): 8836.

DOI：10.1038/ncomms9836

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-beta (A beta) precursor protein carrying the pathogenic Swedish mutation. A beta 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. A beta-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that A beta-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss.

• 出版日期2015-11