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The Journal of Neuroscience, February 14, 2007, 27(7):1682-1691; doi:10.1523/JNEUROSCI.3439-06.2007

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Neurobiology of Disease
Synapse-Associated Protein-97 Mediates -Secretase ADAM10 Trafficking and Promotes Its Activity

Elena Marcello,^1 * Fabrizio Gardoni,^1 * Daniela Mauceri,¹ Stefano Romorini,² Andreas Jeromin,³ Roberta Epis,¹ Barbara Borroni,⁴ Flaminio Cattabeni,¹ Carlo Sala,² Alessandro Padovani,⁴ and Monica Di Luca¹

¹Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy, ²Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, 20129 Milan, Italy, ³Center for Learning and Memory, University of Texas at Austin, Austin, Texas 78712, and ⁴Department of Neurological Sciences, University of Brescia, 25125 Brescia, Italy

Correspondence should be addressed to Monica Di Luca, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Email: monica.diluca{at}unimi.it

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.

Key words: ADAM10; SAP97; APP; glutamatergic synapse; Alzheimer's disease; trafficking

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Received Aug. 9, 2006; revised Nov. 30, 2006; accepted Dec. 24, 2006.

Correspondence should be addressed to Monica Di Luca, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Email: monica.diluca{at}unimi.it

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