Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2523-2538 |
| Number of pages | 16 |
| Journal | Journal of Clinical Investigation |
| Volume | 123 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 3 2013 |
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ASJC Scopus subject areas
- Medicine(all)
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Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease. / Marcello, Elena; Saraceno, Claudia; Musardo, Stefano; Vara, Hugo; De La Fuente, Alerie Guzman; Pelucchi, Silvia; Di Marino, Daniele; Borroni, Barbara; Tramontano, Anna; Pérez-Otaño, Isabel; Padovani, Alessandro; Giustetto, Maurizio; Gardoni, Fabrizio; Di Luca, Monica.
In: Journal of Clinical Investigation, Vol. 123, No. 6, 03.06.2013, p. 2523-2538.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease
AU - Marcello, Elena
AU - Saraceno, Claudia
AU - Musardo, Stefano
AU - Vara, Hugo
AU - De La Fuente, Alerie Guzman
AU - Pelucchi, Silvia
AU - Di Marino, Daniele
AU - Borroni, Barbara
AU - Tramontano, Anna
AU - Pérez-Otaño, Isabel
AU - Padovani, Alessandro
AU - Giustetto, Maurizio
AU - Gardoni, Fabrizio
AU - Di Luca, Monica
PY - 2013/6/3
Y1 - 2013/6/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878556106&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878556106&partnerID=8YFLogxK
U2 - 10.1172/JCI65401
DO - 10.1172/JCI65401
M3 - Article
C2 - 23676497
AN - SCOPUS:84878556106
VL - 123
SP - 2523
EP - 2538
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -