Synapse-Associated Protein-97 Mediates α-Secretase ADAM10 Trafficking and Promotes Its Activity

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder caused by a combination of events impairing normal neuronal function. Here we found a molecular bridge between key elements of primary and secondary pathogenic events in AD, namely the elements of the amyloid cascade and synaptic dysfunction associated with the glutamatergic system. In fact, we report that synapse-associated protein-97 (SAP97), a protein involved in dynamic trafficking of proteins to the excitatory synapse, is responsible for driving ADAM10 (a disintegrin and metalloproteinase 10, the most accredited candidate for ␣-secretase) to the postsynaptic membrane, by a direct interaction through its Src homology 3 domain. NMDA receptor activation mediates this event and positively modulates ␣-secretase activity. Furthermore, perturbing ADAM10/SAP97 association in vivo by cell-permeable peptides impairs ADAM10 localization in postsynaptic membranes and consequently decreases the physiological amyloid precursor protein (APP) metabolism. Our findings indicate that glutamatergic synapse activation through NMDA receptor promotes the non-amyloidogenic APP cleavage, strengthening the correlation between APP metabolism and synaptic plasticity.

SAP97-mediated local trafficking is altered in Alzheimer disease patients' hippocampus

“…Triton insoluble fraction (TIF), a fraction highly enriched in all categories of postsynaptic density proteins (i.e., receptor, signaling, scaffolding, and cytoskeletal elements) absent of presynaptic markers, and soluble fraction S2, were obtained as previously described (Gardoni et al, 2001;Marcello et al, 2007). In order to avoid protein degradation, AD samples were paired to HC samples and processed at the same time.…”

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

“…Marcello et al reported that synapseassociated protein-97, a protein involved in dynamic traffi cking of proteins to the excitatory synapse, drives ADAM10 to the postsynaptic membrane in dendritic spines (Marcello et al , 2007 ). Interestingly, they demonstrated that NMDAR activity directly mediates this event and positively modulates α -secretase activity.…”

“…Moreover, excessive NMDAR activity was shown to contribute importantly to the etiology of many acute or chronic neurodegenerative disorders such as stroke, Hungtinton ' s disease, HIV-associated dementia and AD (Lipton and Rosenberg , 1994 ;Lancelot and Beal , 1998 ). Several studies reported a direct link between NMDAR overactivation on the one hand, and APP processing and neuronal A β secretion on the other hand, even if the conclusions could be somewhat different (Lesn é et al, 2005 ;Marcello et al , 2007 ;Hoey et al , 2009 ). It was further demonstrated that the cellular location of NMDARs is a key parameter controlling their effect on neuronal viability.…”

Activation of NMDA Receptors Upregulates A Disintegrin and Metalloproteinase 10 via a Wnt/MAPK Signaling Pathway

“…Retinoic acid receptors can increase the expression of ADAM10, leading to a decrease in A␤ peptides (Tippmann et al, 2009;Donmez et al, 2010). The activity of ADAM10 is regulated by NMDA receptors (NMDARs), which modulate synaptic trafficking of ADAM10 via synapse-associated protein-97 (SAP97) (Marcello et al, 2007). Interference of the interaction between ADAM10 and SAP97 causes sporadic AD (Epis et al, 2010).…”