. Synaptic autoregulation by metalloproteases and γ-secretase. J Neurosci. 2011 Aug 24;31(34):12083-93. PubMed.

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  1. The news article states that "γ-secretase appears primarily in endosomes," but the results of Area-Gomez et al. (Area-Gomez et al., 2009) do not support this. Most of the γ-secretase activity (at least in neurons) appears to be in the mitochondrial associated membranes (aka "MAM"). In a second paper (Schon and Area-Gomez, 2010), they describe why this has not previously been observed.

    View all comments by Michael Lardelli
  2. The interesting work by Restituito et al. shows that both metalloproteinase and γ-secretase activities are localized at the synapse and regulate synaptic function. These findings, combined with previous reports that PS1 FAD mutations cause loss of γ-secretase function (Marambaud et al. 2003; Georgakopoulos et al. 2006; Litterst et al., 2007), may provide a link between the dysfunction of these proteolytic systems and the synaptic abnormalities of FAD.

    The authors present evidence that components of γ-secretase localize on synaptic membranes where this enzymatic system exerts its proteolytic function, a finding consistent with previous observations of the synaptic localization of PS1 (Georgakopoulos et al., 1999). Interestingly, the experiments with δ-catenin knockout neurons suggest that this catenin mediates the association of PS1 with post-synaptic densities, a finding consistent with reports that δ/p120-catenin, a cadherin-binding protein, binds PS1 and acts as an adaptor that recruits cadherins to γ-secretase for processing (Kouchi et al., 2009). Interestingly, what δ/p120 catenin does for the γ-secretase processing of cadherins, GSAP performs for the γ-secretase processing of APP (He et al., 2010).

    The reported work presented here nicely dissects the role of the two proteolytic activities on synaptic function, showing that they differentially affect glutamatergic transmission, a finding consistent with recent reports that γ-secretase regulates glutamate release (Pratt et al., 2011). Together, these findings provide a potential mechanism of how deregulation of those proteolytic activities may impair synaptic function in AD.

    Overall, the interesting work by Restituito et al. provides evidence for the synaptic localization of both metalloproteinase and γ-secretase activities, and shows that they affect synaptic function. Combined with literature, the work suggests that malfunctions in those proteolytic systems may be involved in the synaptic impairments observed in AD.

    References:

    . A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 2003 Sep 5;114(5):635-45. PubMed.

    . Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J. 2006 Mar 22;25(6):1242-52. PubMed.

    . Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J Biol Chem. 2007 Jun 1;282(22):16155-63. PubMed.

    . Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol Cell. 1999 Dec;4(6):893-902. PubMed.

    . p120 catenin recruits cadherins to gamma-secretase and inhibits production of Abeta peptide. J Biol Chem. 2009 Jan 23;284(4):1954-61. PubMed.

    . Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature. 2010 Sep 2;467(7311):95-8. PubMed.

    . Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling. Nat Neurosci. 2011 Sep;14(9):1112-4. PubMed.

  3. Restituito and colleagues provide interesting and compelling evidence that α-secretase/matrix metalloproteases (MMPs) and γ-secretase lead to a suppression of synaptic activity. NMDA receptors increase enzymatic activity of α-secretase. α-secretase cleaves N-cadherin, which leads to further cleavage by γ-secretase. The consequence of this is destabilized synapses and suppressed synaptic activity (or at the very least, suppressed mini-excitatory post-synaptic currents). Several groups have localized various ADAM secretases and MMP proteins to synapses as well as components of the γ-secretase complex. This paper includes a very elegant localization of all of these proteins to both pre- and post-synaptic compartments using biochemistry, histology, and electron microscopy. It also includes evidence that γ-secretase activity (not just proteins) is present at synapses, though the subcellular localization of γ-secretase activity at the synapse still needs further refinement. They also include nice data that δ-cadherin tethers γ-secretase near the synapse.

    NMDARs, α-secretase, γ-secretase, and MMPs are also responsible for Aβ metabolism (aspects of Aβ generation and Aβ clearance). Oligomeric Aβ appears to reduce synaptic activity. Roberto Malinow’s group has shown that Aβ can have an autoregulatory effect on synaptic activity. Restituito and colleagues propose the NMDAR/N-cadherin/secretase pathway also has a negative autoregulatory effect on activity. Both of these autoregulatory mechanisms would involve NMDARs. There are conceivable scenarios whereby NMDARs could simultaneously decrease Aβ generation to increase synaptic activity, while increasing N-cadherin cleavage to decrease synaptic activity. How NMDARs, secretases, MMPs, cadherins, and Aβ function in various combinations to regulate synaptic activity will be important to parse apart, though the relationships are likely to be very complex (and at the moment are mind boggling to me).

    We have data recently published in that activation of NMDARs increase α-secretase activity, which reduces Aβ generation in vivo (Verges et al., 2011). Restituito et al. show NMDARs increase α-secretase, which leads to N-cadherin-dependent suppression of synaptic activity. It will be interesting to determine if these phenomena share the same initial signaling pathway through α-secretase but result in distinct consequences.

    References:

    . Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo. J Neurosci. 2011 Aug 3;31(31):11328-37. PubMed.

  4. Very interesting results from Restituito and colleagues. It is time to move forward and find out new alternatives to complement the classic amyloid cascade hypothesis of AD.