The Journal of clinical investigation, 2013-06, Vol.123 (6), p.2523-2538
2013
Details
- Autor(en) / Beteiligte
- Titel
- Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease
- Ist Teil von
- The Journal of clinical investigation, 2013-06, Vol.123 (6), p.2523-2538
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- EZB Free E-Journals
- Beschreibungen/Notizen
- A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/jci65401Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3668814
- Format
- –
- Schlagworte
- ADAM Proteins, ADAM Proteins - chemistry, ADAM Proteins - genetics, ADAM Proteins - metabolism, ADAM10 Protein, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Signal Transducing - metabolism, Alzheimer Disease, Alzheimer Disease - enzymology, Alzheimer Disease - pathology, Alzheimer's disease, Amino Acid Motifs, Amino Acid Sequence, Amyloid beta-Protein Precursor, Amyloid beta-Protein Precursor - metabolism, Amyloid Precursor Protein Secretases, Amyloid Precursor Protein Secretases - chemistry, Amyloid Precursor Protein Secretases - genetics, Amyloid Precursor Protein Secretases - metabolism, Animals, Biochemistry, Molecular Biology, Biomedical research, Cell Membrane, Cell Membrane - enzymology, Cercopithecus aethiops, Cognitive science, COS Cells, Development and progression, Endocytosis, Experiments, Fatty Acid-Binding Proteins, Fatty Acid-Binding Proteins - chemistry, Fatty Acid-Binding Proteins - metabolism, Genetic aspects, Hippocampus, Hippocampus - enzymology, Humans, Life Sciences, Long-Term Potentiation, Long-Term Synaptic Depression, Membrane Proteins, Membrane Proteins - chemistry, Membrane Proteins - genetics, Membrane Proteins - metabolism, Metalloenzymes, Mice, Models, Molecular, Molecular Sequence Data, Neuronal Plasticity, Neuroplasticity, Neuroscience, Physiological aspects, Protein Binding, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Transport, Proteins, Software, Synapses, Synapses - enzymology