Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease
Copyright policy )Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease
AbstractAlzheimer’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.
- UNSW Sydney Australia
- University of Wollongong Australia
- Neuroscience Research Australia Australia
Male, 571, Fluorescent Antibody Technique, Enzyme-Linked Immunosorbent Assay, Neural Cell Adhesion Molecule L1, Hippocampus, Article, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, Cell Adhesion, Animals, Humans, Cells, Cultured, Aged, Aged, 80 and over, Cerebral Cortex, Brain, Dynamic Light Scattering, Case-Control Studies, Gene Knockdown Techniques, Female
Male, 571, Fluorescent Antibody Technique, Enzyme-Linked Immunosorbent Assay, Neural Cell Adhesion Molecule L1, Hippocampus, Article, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, Cell Adhesion, Animals, Humans, Cells, Cultured, Aged, Aged, 80 and over, Cerebral Cortex, Brain, Dynamic Light Scattering, Case-Control Studies, Gene Knockdown Techniques, Female
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