Abstract
A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation. Its activity depends on correct intracellular trafficking and on synaptic membrane insertion. Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes. This process is mediated by a previously uncharacterized protein kinase C phosphosite in SAP97 SRC homology 3 domain that modulates SAP97 association with ADAM10. Such mechanism is essential for ADAM10 trafficking from the Golgi outposts to the synapse, but does not affect ADAM10 transport from the endoplasmic reticulum. Notably, this process is altered in Alzheimer's disease brains. These results help in understanding the mechanism responsible for the modulation of ADAM10 intracellular path, and can constitute an innovative therapeutic strategy to finely tune ADAM10 shedding activity towards APP.
Highlights
97 (SAP97), a member of the membrane-associated guanylate kinase family of protein scaffolds that govern the trafficking of glutamate receptors, as an a disintegrin and metalloproteinase 10 (ADAM10) partner
We first verified the effect of protein kinase C (PKC) activation on ADAM10/synapse-associated protein-97 (SAP97) interaction by bioluminescence resonance energy transfer (BRET) experiments
Co-immunoprecipitation (IP) assays from hippocampal slices revealed a significant increase in ADAM10/SAP97 binding 30 min after PKC activation and showed that it occurs in a specific compartment, that is, the Triton-insoluble fraction (TIF), a synaptic and cellular membrane subfraction 16 (Figures 1c and d)
Summary
97 (SAP97), a member of the membrane-associated guanylate kinase family of protein scaffolds that govern the trafficking of glutamate receptors, as an ADAM10 partner. SAP97 binds to the proline-rich sequences of the ADAM10 cytosolic domain with its SRC homology 3 (SH3) domain, thereby driving the protease to the postsynaptic membrane and increasing α-secretase cleavage.[6] Interestingly, the ADAM10/SAP97 interaction is reduced in the hippocampus of AD patients[7] and the disruption of ADAM10/SAP97 association in rodents leads to the generation of a non-transgenic model of the disease.[8] On the other hand, ADAM10 membrane retrieval is mediated by an AP2-clathrin-dependent mechanism implicated in the dynamic regulation of ADAM10 synaptic localization/activity.[9] All these data claim for a role of ADAM10 trafficking in the pathogenesis of AD Despite this knowledge, the intracellular signaling pathways regulating ADAM10 trafficking are still explored limitedly.
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