ABSTRACT
Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti 9, 20133 Milan, Italy
Pharmacotoxicological and Pharmacognostic Sciences and Pharmacological Biotechnologies
ADAM10 (a disintegrin and metalloproteinase10) is the most accredited candidate as alpha-secretase in the amyloid cascade, since it prevents Abeta formation. ADAM10 is synthesized in an inactive form, which is proteolytically activated during its forward transport along the secretory pathway and at the plasma membrane. Therefore, modulation of its trafficking could provide a mechanism to finely tune its activity. We reported that ADAM10 interacts directly with SAP97, a protein involved in trafficking of glutamate receptors, and this interaction is required for ADAM10 localization and enzymatic activity at postsynaptic membranes. It has been shown that PKC activation stimulates alpha-secretase activity and inhibits the secretion of Abeta. In particular, Alzheimer's disease patients have been reported tohave lower levels of PKC activity. Moreover, PKC activity may regulatethe subcellular localization of ADAM10.
In this framework, the aim of our study is to investigate the involvement of ADAM10/SAP97 complex in the mechanism underlying PKC-induced alpha-secretase activation.
Here we report that 30 minutes in vitro PKC activation via Phorbol 12,13-Dibutyrate (PDBu) induces an increase of ADAM10 levels in the postsynaptic compartment and a parallel reduction of enzyme level in the microsomal fraction.To evaluate the role of ADAM10/SAP97 complex in ADAM10 secretory trafficking, we took advantage of a cell-permeable peptide, Tat-Pro ADAM10709-729, which mimics the proline-rich region of ADAM10, responsible for its association to SAP97 and consequently interferes with ADAM10/SAP97 interaction. The treatment with the Tat-Pro ADAM10709-729 peptide is able to prevent PDBu-induced ADAM10 trafficking to the postsynaptic compartment, suggesting an involvement of SAP97. A step forward will be the understanding of the mechanism underlying this effect, which may have a functional implication for the regulation of alpha-secretase activity.