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Synaptic autoregulation by metalloproteases and γ-secretase.

The proteolytic machinery comprising metalloproteases and γ-secretase, an intramembrane aspartyl protease involved in Alzheimer's disease, cleaves several substrates in addition to the extensively studied amyloid precursor protein. Some of these substrates, such as N-cadherin, are synaptic proteins involved in synapse remodeling and maintenance. Here we show, in rats and mice, that metalloproteases and γ-secretase are physiologic regulators of synapses. Both proteases are synaptic, with γ-secretase tethered at the synapse by δ-catenin, a synaptic scaffolding protein that also binds to N-cadherin and, through scaffolds, to AMPA receptor and a metalloprotease. Activity-dependent proteolysis by metalloproteases and γ-secretase takes place at both sides of the synapse, with the metalloprotease cleavage being NMDA receptor-dependent. This proteolysis decreases levels of synaptic proteins and diminishes synaptic transmission. Our results suggest that activity-dependent substrate cleavage by synaptic metalloproteases and γ-secretase modifies synaptic transmission, providing a novel form of synaptic autoregulation.

Pubmed ID: 21865451 RIS Download

Mesh terms: Amyloid Precursor Protein Secretases | Animals | Catenins | Cells, Cultured | Female | Hippocampus | Homeostasis | Male | Metalloproteases | Mice | Mice, Knockout | Rats | Rats, Sprague-Dawley | Synapses | Synaptic Membranes | Synaptic Transmission

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Associated grants

  • Agency: NIA NIH HHS, Id: R37 AG013620-17
  • Agency: NINDS NIH HHS, Id: R01 NS35527
  • Agency: NIA NIH HHS, Id: R37 AG013620-23
  • Agency: NINDS NIH HHS, Id: R01 NS035527-12
  • Agency: NIA NIH HHS, Id: R37 AG013620-16
  • Agency: NIA NIH HHS, Id: R37 AG013620-22
  • Agency: NIA NIH HHS, Id: R01 AG013620
  • Agency: NIA NIH HHS, Id: R37 AG013620-20
  • Agency: NIA NIH HHS, Id: R37 AG013620
  • Agency: NIA NIH HHS, Id: P01 AG017617
  • Agency: NINDS NIH HHS, Id: R01 NS035527
  • Agency: NIA NIH HHS, Id: R37 AG013620-21
  • Agency: NIA NIH HHS, Id: R37 AG013620-18
  • Agency: NIA NIH HHS, Id: R37 AG013620-19
  • Agency: NIA NIH HHS, Id: R37 AG13620
  • Agency: NIA NIH HHS, Id: P01 AG017617-10

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