title: Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease.
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.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Iryna
authors.initials: I
authors.lastname: Leshchyns'ka
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Heng Tai
authors.initials: HT
authors.lastname: Liew
authors.affiliation: Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Shepherd
authors.affiliation: Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.
authors.forename: Glenda M
authors.identifier: http://orcid.org/0000-0003-0422-8398
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.|Dementia Research Unit, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Stevens
authors.affiliation: Dementia Research Unit, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Yazi D
authors.initials: YD
authors.lastname: Ke
authors.affiliation: Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.|Dementia Research Unit, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Vladimir
authors.identifier: http://orcid.org/0000-0003-1927-2199
authors.initials: V
authors.lastname: Sytnyk
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002448:Cell Adhesion; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000067493:Dynamic Light Scattering; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D016564:Amyloid beta-Protein Precursor; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D018091:Receptors, AMPA; C108033:NCAM2 protein, human; C108768:Ncam2 protein, mouse