Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity.
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.
Marcello
Elena
E
Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy.
Gardoni
Fabrizio
F
Mauceri
Daniela
D
Romorini
Stefano
S
Jeromin
Andreas
A
Epis
Roberta
R
Borroni
Barbara
B
Cattabeni
Flaminio
F
Sala
Carlo
C
Padovani
Alessandro
A
Di Luca
Monica
M
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
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