Several neurodegenerative disorders, including Alzheimer’s disease, arise when protein-cutting enzymes process proteins in the wrong way. The resulting protein fragments can accumulate in nerve cells and cause them to die, leading to symptoms such as memory loss. In the case of Alzheimer’s disease the toxic protein fragment – called amyloid beta – can be produced when one enzyme cuts the amyloid precursor protein. However, the amyloid beta fragment is not made when a different enzyme called ADAM10 cuts the amyloid precursor protein first.

There has been a lot of interest in finding drugs that activate ADAM10 to treat Alzheimer’s disease. However, ADAM10 also cuts other proteins on the surface of cells and it is important to know about these proteins if ADAM10 is going to be successfully targeted by a drug.

To tackle this issue, Kuhn et al. have now searched for new proteins (or ‘substrates’) that are cut by ADAM10 in mouse nerve cells. The experiments identified proteins that were cut in normal nerve cells, but remained unprocessed in cells where the gene for ADAM10 had been deleted. This search uncovered almost 100 new substrates of ADAM10 that were then validated using biochemical techniques.

Among these substrates were many proteins that are normally anchored into the membranes of nerve cells and involved in guiding and positioning these cells in the brain so that they can connect and communicate with each other. Kuhn et al. then deleted the gene for ADAM10 only in the frontmost part of the mouse brain. This led to the nerve cells forming abnormal networks in the regions of the brain that process smells and emotions. Overall the experiments proved that ADAM10 is important not only for the prevention of Alzheimer’s disease, but also for the normal development of the brain. Future studies could now explore how stimulating ADAM10 affects the levels of its substrates. Also, a better understanding of the substrates of ADAM10 may be useful both to predict side effects of drugs that activate ADAM10 and to monitor patients who are responding well to these drugs.

Proteolysis of cell surface membrane proteins is a basic cellular mechanism that controls intercellular communication and the interaction of cells with their extracellular environment. Proteolysis typically occurs close to the luminal or extracellular side of the membrane and results in release of the membrane protein’s ectodomain. This process, referred to as ectodomain shedding, is a mechanism that shapes the cell surface by controlling the ectodomain length of cell surface membrane proteins thus modulating their function (Weber and Saftig, 2012).

Membrane-bound metalloproteases of the metzincin family have a key role in catalyzing ectodomain shedding of membrane proteins, in particular members of the ‘a disintegrin and metalloprotease’ (ADAM) subfamily (Weber and Saftig, 2012). One of them is ADAM10, which is a ubiquitously expressed type I membrane protein whose active site is located within its ectodomain, well positioned to shed the ectodomains of its substrates (Weber and Saftig, 2012). A key substrate for ADAM10 is the Notch receptor, which requires ADAM10-mediated shedding for its signaling during differentiation and development (Hartmann et al., 2002; Qi et al., 1999). Consequently, constitutive ADAM10-deficient mice die at embryonic day 9.5 most likely due to a loss of Notch signaling (Hartmann et al., 2002). Another major substrate of ADAM10 is the amyloid precursor protein (APP) for which ADAM10 acts as the constitutive alpha-secretase (Postina et al., 2004; Lammich et al., 1999; Kuhn et al., 2010; Jorissen et al., 2010) and thus possesses the ability to prevent the generation of the pathogenic Aβ peptide in Alzheimer’s disease (AD) (Lammich et al., 1999; Kuhn et al., 2010). This makes ADAM10 a major drug target for AD (Postina et al., 2004), and an activator of ADAM10 expression has been tested in a clinical trial for AD (Endres et al., 2014). Whether such a therapeutic approach is safe, remains to be seen, in particular because relatively little is known about ADAM10 substrates in brain.

Besides Notch and APP, additional ADAM10 substrates, such as E-cadherin and CX3CL1, have been identified in different organs and tissues (Hundhausen et al., 2003). Given the embryonically lethal phenotype of constitutive ADAM10-deficient mice, little is known about ADAM10 substrates in the central nervous system (Hartmann et al., 2002). A few ADAM10 substrates have been identified in the brain. Some of them have neuronal and synaptic functions, such as APP (Ring et al., 2007; Weyer et al., 2011; 2014), Neuroligin-1 (Blundell et al., 2010; Kim et al., 2008) or N-Cadherin, which is in line with the phenotypes reported for conditional ADAM10-/- mice lacking ADAM10 expression in most neurons (Jorissen et al., 2010; Gibb et al., 2010; Prox et al., 2013). While these mice circumvent ADAM10 dependent embryonic lethality, they show epileptic seizures, learning deficits and an altered morphology of postsynaptic structures in the brain and die postnatally. This demonstrates that ADAM10 is essential for synaptic and neuronal network functions in the mouse brain (Jorissen et al., 2010; Prox et al., 2013).

Yet, the known ADAM10 substrates only partly explain these phenotypes and more ADAM10 substrates are expected to exist in brain. Their identification will allow a better mechanistic understanding of ADAM10 function in brain. Moreover, new ADAM10 substrates may be useful as biomarkers to evaluate how a patient responds to an ADAM10-modulating drug, for example in clinical trials for AD.

To systematically identify neuronal ADAM10 substrates, we used the quantitative proteomic ‘secretome protein identification with click sugars’ (SPECS) method, which has already been successfully applied to the identification of substrates for the membrane proteases BACE1 and SPPL3 (Kuhn et al., 2012; 2015). SPECS allows specific enrichment of cell-derived glycoproteins which otherwise would escape detection by mass spectrometry due to their low abundance. Using high-resolution mass spectrometry and label-free quantification we systematically analyzed both the levels of membrane proteins in the neuronal membrane as well as their shed ectodomains in the secretome of primary, murine neurons, either expressing or lacking ADAM10. We identified 91, mostly novel ADAM10 substrate candidates.

Selected substrates, including NRCAM, LDLR, MT4MMP and CDH6 were validated by quantitative immunoblots in neurons and in mouse brain and point to a central function of ADAM10 in synapse formation and axon targeting. In line with this we detected an axon targeting defect in the olfactory bulb of conditional ADAM10-/- mice, similar to what has been observed in mice deficient in the novel ADAM10 substrate NRCAM.

Ectodomain shedding of membrane proteins is a fundamental mechanism to control intercellular communication, the interaction between cells and their environment. Our study demonstrates that ADAM10 is a major shedding enzyme in the nervous system and that a loss of ADAM10 leads to defects in neuronal connectivity.

The metalloprotease ADAM10 plays manifold roles in development and disease. Studying ADAM10 substrates in primary cells or tissue has not been possible until the advent of conditional Adam10 knockout mice as constitutive Adam10 knockout mice die latest at embryonic day 9.5 (E9.5). These mice succumb to malformations like a retarded heart development, extracorporeal formation of blood vessels and improper formation of somites, which are considered to result from a lack in proteolytic processing of Notch by ADAM10 (Hartmann et al., 2002; Jorissen et al., 2010; Krebs et al., 2000; Kageyama and Ohtsuka, 1999). However, postnatal neuron-specific disruption of Adam10 in the brain leads to impaired learning, defects in long term potentiation and seizures which are considered to result from defects in synapse function and architecture and microglial and astrocytic activation (Prox et al., 2013). These phenotypes point to an important postnatal function of ADAM10 via cleavage of additional substrates beyond Notch. So far, Notch and other ADAM10 substrates like N-Cadherin, fractalkine, Neuroligin-1 or E-Cadherin have already been described (Hundhausen et al., 2003; Suzuki et al., 2012; Reiss et al., 2005; Maretzky et al., 2005). However, only few substrates like N-Cadherin, Neuroligin-1, Notch-1 and Notch-2 have been shown to be cleaved in primary cells like neurons due to the aforementioned embryonic lethality of constitutive Adam10 knockout mice and the lack of conditional Adam10 knockout models until recently (Prox et al., 2013; Suzuki et al., 2012; Zheng et al., 2012).

Here, we provide the first systematic analysis of ADAM10 substrates in primary cortical neurons of a conditional Adam10 knockout mouse. Applying SPECS to enrich newly synthesized glycoproteins from conditioned media and the cell surface of primary neurons we identified more than 300 glycoproteins in the secretome, which is slightly more than in our previous study identifying BACE1 substrates in neurons (Kuhn et al., 2012). Additionally, we identified and quantified more than 400 membrane glycoproteins on or close to the cell surface of neurons which is 10 times more membrane proteins than in a previous study where cell surface biotinylation was used, but without the SPECS labeling (Sanz et al., 2015). This demonstrates the power of the metabolic SPECS labeling to an in-depth quantification of the neuronal membrane proteome. Our analysis revealed that almost 50% of all membrane proteins released into the secretome are reduced upon Adam10 deletion of which 70% possess a type-I topology. Furthermore, we found that 13 secreted proteins like clusterin were reduced. Because ADAM10 cleaves membrane-bound substrates, the reduced clusterin levels are likely to be the consequence of secondary effects such as an increased internalization due to stabilization of its surface receptor in ADAM10-deficient neurons. The large number of substrates makes ADAM10 a major sheddase in the nervous system and an important modifier of the neuronal secretome. Among the candidate ADAM10 substrates in the secretome we could identify whole protein families having roles in synapse function and architecture. Their reduced cleavage upon Adam10 deletion fits to the phenotypes described in neuron-specific conditional Adam10 knockout mice, including defects in long term potentiation and seizures (Prox et al., 2013). For example, Neurexins and Neuroligins are known to form trans-synaptic complexes which are especially necessary for synapse function (Figure 7) (Bang and Owczarek, 2013; Südhof, 2008). Adam10 ablation caused a strong reduction in ectodomain shedding of postsynaptic NLGN1, 3 and slightly less pronounced for NLGN4. Hence, shedding of Neuroligins might negatively regulate their synaptic function (Suzuki et al., 2012). Surprisingly, NLGN2 shedding was not affected by Adam10 deletion, which might be explained by the distinct roles played by these proteins. In fact, NLGN1 and 3 contribute to the function of excitatory, glutamatergic synapses while NLGN2 contributes to the function of inhibitory, GABAergic synapses (Kang et al., 2014) suggesting that ADAM10 might preferably be involved in the modulation of glutamatergic, excitatory but not GABAergic inhibitory synapse functions. This is additionally supported by the fact that the ionotropic glutamate receptor GLUR1 (Gria1), previously described to be modulated by synaptic NLGN1 levels (Wittenmayer et al., 2009), was increased in the cellular glycoproteome upon Adam10 deletion while GABA receptors which are known to interact with NLGN2 were not increased (Kang et al., 2014). Besides the reduction of NLGN1, 3 and 4 shedding, Adam10 deletion resulted in a concomitant shedding reduction of the NLGN receptors NRXN 2 and 3 while the full length NRXN precursors mildly accumulated in the cellular glycoproteome. We additionally observed reduced ectodomain shedding for almost all members of the receptor tyrosine phosphatase family (PTPR) and the Slit and receptor tyrosine kinase domain (SLITRK) family which both play roles in synapse function and formation (Figure 7) (Um et al., 2014; Yim et al., 2013). Specific members of both families like for example PTPRD and SLITRK3 have been shown to interact with each other transsynaptically (Um et al., 2014; Takahashi et al., 2012). While SLITRK1, 2, 4 and 5 and PTPRS have been implicated in the formation of excitatory synapses, SLITRK3 and PTPRD seem to be involved in the formation of inhibitory synapses (Yim et al., 2013).

Figure 7

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Impaired cognitive functions can also result from impaired axon targeting and function leading to impaired signal transmission and wrong connection of cortical regions in the brain. We observed mistargeted axons of the olfactory epithelium projecting instead of usually to one olfactory glomerulus to two olfactory glomeruli in the olfactory bulb of ADAM10-deficient mice. Similar axon targeting phenotypes have also been reported upon knock-out of L1 family members Nrcam and Chl1 while L1 knockout mice succumb to the much more severe CRASH syndrome with corpus callosum hypoplasia and mental retardation (Heyden et al., 2008; Montag-Sallaz et al., 2002; Demyanenko et al., 2011; Kolata et al., 2008). Indeed, we observed reduced ectodomain shedding of all L1 family members (L1, CHL1, NRCAM and Neurofascin (NFASC)) with NRCAM shedding being reduced the strongest. In contrast, shedding of L1 and CHL1, previously identified as major substrates of BACE1 in neurons (Kuhn et al., 2012; Zhou et al., 2012) were only mildly modulated upon ADAM10 knockout in line with previous data that demonstrate cleavage of CHL1 and L1 by metalloproteases in non-neuronal cells (Maretzky et al., 2005; Naus et al., 2004). Simultaneous BACE1 inhibition and Adam10 knockout resulted in a further reduction of ectodomain shedding of CHL1 and L1 in a similar fashion to APP (Colombo et al., 2013; Zhou et al., 2012). While for L1 differential functional outcomes of ADAM10 and BACE1 cleavage have not been investigated so far, it recently has been shown that CHL1 cleavage by BACE1 is indispensible for Semaphorin 3a induced axon repulsion while inhibition of metalloprotease mediated CHL1 cleavage had no impact which suggests that modulation of axon growth in the axonal or presynaptic compartment via CHL1 is only modulated by BACE1 (Barão et al., 2015). Interestingly, as shown here for conditional ADAM10 knockout CamKII-Cre mice, misplaced hippocampal mossy fiber terminals were also observed in CHL1- or NCAM-deficient (Colombo et al., 2013; Yasuda et al., 2007) but also in BACE1-deficient mice (Hitt et al., 2012). Likewise, CHL1-, NrCAM-, BACE1-, or ADAM10-deficiency all result in mistargeted axons in olfactory glomeruli (Montag-Sallaz et al., 2002), which may indicate functions for the refinement of connectivity (Montag-Sallaz et al., 2002). Nevertheless, other identified substrates, such as neogenin (NEO1) and contactin-2 (CNTN2) may also contribute (Denaxa et al., 2005; Braisted et al., 2000), which makes a substrate phenotype correlation difficult.

Conditional Adam10 knockout mice also show activated microglia upon postnatal, neuronal deletion of Adam10 (Prox et al., 2013). One important chemokine expressed by neurons is fractalkine (CX3CL1) which has previously been proposed to be cleaved by ADAM10 and ADAM17 (Hundhausen et al., 2003; Garton et al., 2001). Abolished constitutive shedding of CX3CL1 and increased CX3CL1 full length protein levels in neurons upon knockout of ADAM10 demonstrate that ADAM10 regulates CX3CL1 levels in neurons (Figure 3B). The biological role of ADAM10 cleaved soluble CX3CL1 might be a reduction of microglial activation leading to neuroprotection. This is supported by the finding that microglial activation and neuronal cell death in the substantia nigra upon MPTP treatment are increased in a CX3CL1 knockout mouse model and can be rescued by soluble but not membrane bound CX3CL1 suggesting a neuroprotective role of soluble CX3CL1 (Ueno et al., 2013; Nash et al., 2013; Morganti et al., 2012).

We also identified low density lipoprotein receptor (LDLR) as a novel substrate of ADAM10. LDLR has been described to undergo induced release upon treatment with the phorbolester PMA and its c-terminal fragment is subject to intramembrane proteolysis by γ-secretase (Tveten et al., 2013). Here, we show that constitutive shedding of LDLR is catalyzed by ADAM10. Soluble LDLR has been shown to be able to bind to LDL. However, functional consequences of ADAM10 catalyzed cleavage of LDLR like an altered LDL uptake have not been investigated so far.

Another important finding was that in contrast to other proteases like ADAM17 or ADAM9 (Kuhn et al., 2010), cellular levels of the GPI-anchored, neuronally expressed metalloprotease MT4MMP increased while MT4MMP ectodomain shedding was abolished upon Adam10 deletion (Rikimaru et al., 2007). MT4MMP is assumed to mostly cleave soluble proteins in the extracellular matrix (Itoh, 2015). However, since little is known about the physiological substrate spectrum of MT4MMP in neurons, we cannot exclude that some of our observed changes in the ADAM10-/- neurons and their secretome may be an indirect consequence of the reduced MT4MMP shedding.

Our data revealed that some proteins are exclusive substrates of ADAM10 (NRCAM, CX3CL1) while others are exclusively cleaved by BACE1 (SEZ6, APLP1). Finally, there is a group of proteins that can be cleaved by both proteases (APP, CHL1, L1). This specificity may result from differential sorting of the substrates towards the pre- and postsynaptic compartment, or from primary sequence constraints in the juxtamembrane region. However, this classification will be extended in the future as substrates of other in neuron expressed proteases like MT4MMP and MT5MMP have not been determined in the brain yet (Rikimaru et al., 2007; Jaworski, 2000).

Taken together, the identification of novel ADAM10 substrates demonstrates that ADAM10 has a large spectrum of neuronal substrates, but the ADAM10 substrate repertoire is presumably even larger. For example Notch1, an established ADAM10 substrate, was not detected in our analysis, potentially because its expression level was below the detection limit or because it was not expressed in the neurons at the time-point of analysis or because its ADAM10-mediated shedding is ligand-dependent. Additionally, while we identified ADAM10 substrates in neurons, ADAM10 is also expressed in astrocytes and oligodendrocytes and certain proteins are expressed at later developmental stages than what we have investigated (Sakry et al., 2014; Ludwig et al., 2005). Furthermore, it is possible that certain biological effects of Adam10 deletion cannot be investigated in dissociated in vitro cultures of neurons but require the context of brain tissue to provide the correct extracellular matrix and tissue architecture, which is provided by slice cultures or even better in vivo.

In summary, our study demonstrates that ADAM10 is a major sheddase in the brain and is required for correct axon targeting in the olfactory bulb and the hippocampus of conditional ADAM10-/- mice. The newly identified substrates demonstrate that ADAM10 has a fundamental role in the brain and provide a molecular explanation for cognitive deficits, seizures and axon mistargeting in neuron-specific ADAM10 knockout mice. Finally, these findings will also aid the prediction of potential side effects of ADAM10-activating drugs as they are considered for the treatment of AD and prion disease.

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Author details

1. Peer-Hendrik Kuhn

   1. Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
   2. Institut für Pathologie und Pathologische Anatomie, Technische Universität München, Munich, Germany
   3. Institute for Advanced Study, Technische Universität München, Munich, Germany

   Contribution

   P-HK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   peerhendrik@gmx.net

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-7891-5102

2. Alessio Vittorio Colombo

   1. Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
   2. Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany

   Contribution

   AVC, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Benjamin Schusser

   Department of Animal Science, Institute for Animal Physiology, Ludwig-Maximilians-Universität München, Munich, Germany

   Contribution

   BS, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

4. Daniela Dreymueller

   Institute of Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany

   Contribution

   DD, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Sebastian Wetzel

   Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany

   Contribution

   SW, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

6. Ute Schepers

   Karlsruhe Institute of Technology, Karlsruhe, Germany

   Contribution

   US, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

7. Julia Herber

   1. Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
   2. Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany

   Contribution

   JH, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

8. Andreas Ludwig

   Institute of Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany

   Contribution

   AL, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

9. Elisabeth Kremmer

   German Research Center for Environmental Health, Institute of Molecular Tumor immunology, Helmholtz Zentrum München, Munich, Germany

   Contribution

   EK, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

10. Dirk Montag

    Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany

    Contribution

    DM, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-4964-1330

11. Ulrike Müller

    Department of Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany

    Contribution

    UM, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

12. Michaela Schweizer

    Service-Gruppe für Elektronenmikroskopie, Zentrum für Molekulare Neurobiologie, Hamburg, Germany

    Contribution

    MS, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

13. Paul Saftig

    Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany

    Contribution

    PS, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

14. Stefan Bräse

    Karlsruhe Institute of Technology, Karlsruhe, Germany

    Contribution

    SB, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

15. Stefan F Lichtenthaler

    1. Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    2. Institute for Advanced Study, Technische Universität München, Munich, Germany
    3. Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany
    4. Munich Cluster for Systems Neurology, Munich, Germany

    Contribution

    SFL, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    stefan.lichtenthaler@dzne.de

    Competing interests

    The authors declare that no competing interests exist.

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