title: Synapse-associated protein-97 mediates alpha-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 alpha-secretase) to the postsynaptic membrane, by a direct interaction through its Src homology 3 domain. NMDA receptor activation mediates this event and positively modulates alpha-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.
authors.affiliation: Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Marcello
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.forename: Daniela
authors.initials: D
authors.lastname: Mauceri
authors.forename: Stefano
authors.initials: S
authors.lastname: Romorini
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeromin
authors.forename: Roberta
authors.initials: R
authors.lastname: Epis
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.forename: Flaminio
authors.initials: F
authors.lastname: Cattabeni
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000074288:Discs Large Homolog 1 Protein; D004622:Embryo, Mammalian; D005455:Fluorescent Antibody Technique / Q000379:methods; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human