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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.

Pubmed ID: 17301176


  • Marcello E
  • Gardoni F
  • Mauceri D
  • Romorini S
  • Jeromin A
  • Epis R
  • Borroni B
  • Cattabeni F
  • Sala C
  • Padovani A
  • Di Luca M


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

February 14, 2007

Associated Grants


Mesh Terms

  • ADAM Proteins
  • Adaptor Proteins, Signal Transducing
  • Amyloid Precursor Protein Secretases
  • Animals
  • Cells, Cultured
  • Cercopithecus aethiops
  • Embryo, Mammalian
  • Fluorescent Antibody Technique
  • Hippocampus
  • Humans
  • Immunoprecipitation
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Neurons
  • Protein Structure, Tertiary
  • Protein Transport
  • RNA, Small Interfering
  • Rats
  • Receptors, N-Methyl-D-Aspartate
  • Transfection