ABSTRACT
Title
Activity-dependent synaptic plasticity and ADAM10 trafficking
Authors
E. Marcello1, F. Gardoni1, H. Vara-Rivera2, F. Cattabeni1, M. Giustetto3, I. Perez-Otaño4, M. Di Luca Monica1
1Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti 9, 20133 Milan, Italy
2.Instituto de Neurociencias de Alicante, Universidad Miguel Hernández – CSIC. Sant Joan d'Alacant, 03550 Alicante, Spain.
3Dept. of Anatomy, Pharmacology and Forensic Medicine and Istituto Nazionale di Neuroscienze, Torino, Italy
4 Cellular Neurobiology Laboratory, Neuroscience Department, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain.
1Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti 9, 20133 Milan, Italy
2.Instituto de Neurociencias de Alicante, Universidad Miguel Hernández – CSIC. Sant Joan d'Alacant, 03550 Alicante, Spain.
3Dept. of Anatomy, Pharmacology and Forensic Medicine and Istituto Nazionale di Neuroscienze, Torino, Italy
4 Cellular Neurobiology Laboratory, Neuroscience Department, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain.
Abstract
Molecular pathogenesis of neurodegenerative diseases, such as Alzheimer Disease (AD), is the result of a complex interplay of several crossing pathways. Genetic and cell biological studies led to the amyloid hypothesis, which posits that Abeta plays a pivotal role in AD pathogenesis. Besides this process, synaptic abnormalities occurring early in the course of the disease have been described. We have demonstrated a clear relation between the amyloid cascade and synaptic plasticity. We reported that the localization and activity of ADAM10, the protagonist of the non-amyloidogenic pathway of the amyloid cascade, are positively modulated by the interaction with SAP97, a protein involved in trafficking of glutamate receptors.
Here we addressed the effect of activity-dependent synaptic plasticity on ADAM10 trafficking. Long-term potentiation (LTP) and long-term depression (LTD) were induced in acute hippocampal slices using electrophysiological stimulation, and in primary hippocampal cultures using chemical treatments, and then ADAM10 localization was analysed. Induction of LTD leads to the delivery of ADAM10 to the postsynapse associated with an increase of the surface pool of ADAM10. Exposure to the cell permeable peptide Tat Pro, able to disrupt ADAM10/SAP97 association, prevents LTD-induced ADAM10 trafficking and interferes with LTD maintenance.
In contrast, induction of LTP causes an increase of ADAM10 intracellular levels and a concomitant reduction of ADAM10 surface pool, thus suggesting that LTP induction may produce ADAM10 internalization. Indeed, LTP induction increases ADAM10 association to the AP2 clathrin adaptor complex. LTP and LTD had an opposite effect not only on ADAM10 localization, but also on APP metabolism: LTP induction shifted APP processing towards the amyloidogenic pathway, while LTD stimulated the physiologic processing of APP.
Our results suggest a strict interdependence between synaptic plasticity processes and ADAM10 trafficking to the postsynapse. Therefore impairments in the regulation of this mechanism may influence APP metabolism and Abeta production.
Here we addressed the effect of activity-dependent synaptic plasticity on ADAM10 trafficking. Long-term potentiation (LTP) and long-term depression (LTD) were induced in acute hippocampal slices using electrophysiological stimulation, and in primary hippocampal cultures using chemical treatments, and then ADAM10 localization was analysed. Induction of LTD leads to the delivery of ADAM10 to the postsynapse associated with an increase of the surface pool of ADAM10. Exposure to the cell permeable peptide Tat Pro, able to disrupt ADAM10/SAP97 association, prevents LTD-induced ADAM10 trafficking and interferes with LTD maintenance.
In contrast, induction of LTP causes an increase of ADAM10 intracellular levels and a concomitant reduction of ADAM10 surface pool, thus suggesting that LTP induction may produce ADAM10 internalization. Indeed, LTP induction increases ADAM10 association to the AP2 clathrin adaptor complex. LTP and LTD had an opposite effect not only on ADAM10 localization, but also on APP metabolism: LTP induction shifted APP processing towards the amyloidogenic pathway, while LTD stimulated the physiologic processing of APP.
Our results suggest a strict interdependence between synaptic plasticity processes and ADAM10 trafficking to the postsynapse. Therefore impairments in the regulation of this mechanism may influence APP metabolism and Abeta production.