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Department of Neuroscience,1 Department of Neurology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, D.C. 20057-1464,2 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-90463
Received 12 July 2005/ Accepted 8 August 2005
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ABSTRACT |
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- and ß-CTF, and F-spondin reduced the levels of APP intracellular domain signaling, suggesting that there are also intracellular interactions between APP and ApoEr2, perhaps involving adaptor proteins. These studies suggest that the extracellular matrix molecule F-spondin can cluster APP and ApoEr2 together on the cell surface and affect the processing of each, resulting in decreased production of Aß. |
INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- or ß-secretase, resulting in the formation of a large N-terminal extracellular fragment (APPs) and smaller, membrane-bound C-terminal fragments (CTF). If the initial cleavage event occurs via ß-secretase, then cleavage of the CTF by 
-secretase results in the formation of Aß. Recent evidence suggests that F-spondin, a developmentally regulated neuronal protein associated with the extracellular matrix, may act as a regulator of APP processing (8). Specifically, F-spondin binds to the extracellular domain of APP and inhibits ß-secretase cleavage (8). Thus, F-spondin may serve as a regulator of Aß formation. Despite the importance of APP in the formation of ß- amyloid plaques, apolipoprotein E (apoE) remains the best defined genetic risk factor for late-onset AD (27). In AD brains, apoE is a component of most plaques and the APOE genotype correlates with the levels of Aß deposition (23, 27). apoE may affect Aß production, aggregation, or clearance and has been referred to as a pathological chaperone (5, 18, 34). Conversely, apoE may affect the development of AD indirectly through other processes, including cholesterol transport and synapse formation (16), neurite outgrowth (20), or destabilization of microtubules (19).
apoE binds to members of the low-density lipoprotein (LDL) receptor family, including the apoE receptor 2 (ApoEr2) and the LDL receptor-related protein (LRP); each of these receptors binds numerous ligands (26). At the molecular level, ligand interactions with members of this receptor family affect several intracellular signaling pathways, leading to the inhibition of the c-Jun N-terminal kinase 1/2 pathway and the activation of the extracellular signal-regulated kinase 1/2 pathway (9). Interestingly, apoE receptors and APP undergo similar proteolytic cleavage by -secretase, leading to the release of intracellular domains that interact with common adaptor proteins (10, 17). We hypothesize that extracellular ligands of ApoEr2 could affect the processing of APP, either directly or through the modulation of intracellular signaling pathways.
In this work, we demonstrate that F-spondin, in addition to interacting with APP and affecting its processing, also interacts with ApoEr2 and affects its processing. The effects of F-spondin on proteolysis of APP depends on the interaction of F-spondin with apoE receptors. We suggest that there could exist a tripartite complex of APP, F-spondin, and ApoEr2 on the cell surface, affecting processing of the membrane-bound molecules.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell lines and culture conditions. COS7 and HEK293 cells were maintained in Opti-MEM (Invitrogen) with 10% fetal bovine serum (FBS) (Life Technologies, Inc.) in a 10% CO2 incubator. Reelin-, spondin-, thrombospondin-, or full-length F-spondin-conditioned medium and control medium were prepared as described previously (4). Briefly, COS7 cells were transfected with the reelin, spondin, thrombospondin, or F-spondin plasmid or with a pSecTag2/HygroB vector. After 24 h, the cells were transferred to Opti-MEM serum-free medium (Invitrogen). Conditioned media were collected at 48 h posttransfection, concentrated 10- fold with a Centricon centrifugal filter with a 10,000-molecular-weight cutoff (Millipore), and stored at –80°C in small aliquots. Purified receptor-associated protein (RAP) was obtained from Dudley Strickland. Cells were preincubated in the presence of 1 µM RAP overnight and then exposed to either control medium or F-spondin-containing medium for 12 h.
Antibodies.
For transfected cells, we used anti-HA (Abcam) or anti-c-myc (Abcam) antibodies. For analysis of APP, we used 22C11 (identifying the extracellular domain of APP) (Chemicon), 6E10 (identifying secreted APP and ß-CTF) (Signet), and c1/6.1 and 369 (recognizing the C-terminal domain of APP). Anne Cataldo provided c1/6.1, and Sam Gandy provided 369. Antibody R2, against the thrombospondin domain of F-spondin, was provided by Avihu Klar. Antibody 5810 was raised in a rabbit against a recombinant protein of the first three ligand binding repeats of mouse ApoEr2 and does not cross-react with human ApoEr2 (data not shown). ApoEr2 antibody -19, against its C terminus, was kindly provided by Johannes Nimpf.
Quantification of ApoEr2 and APP proteolytic fragments.
COS7 cells were transiently transfected with APP and indicated plasmids or ApoEr2 and indicated plasmids and then cultured in Dulbecco modified Eagle medium containing 10% FBS for 24 h. Cells were maintained for another 24 h in serum-free media with or without F-spondin-derived proteins. Secreted fragments were determined by Western blot analysis of the media (secreted APP, 6E10 antibody; secreted ApoEr2, 5810 antibody). CTF were measured by Western blotting from cell lysates (APP CTF, C1/6.1; APP ß-CTF, 6E10; ApoEr2 CTF, HA antibodies). Aß40 and Aß42 levels in the conditioned media were determined byenzyme-linked immunosorbent assays, using 1A10 (anti-Aß40) or 1C3 (anti-Aß42) as a capture antibody and 12B2, which recognizes both mouse and human Aß as a detection antibody (Immuno-Biological Laboratories) (11).
Primary neuronal cell culture. Primary mouse embryonic cortical neuron cultures were prepared from embryonic day 16 Swiss-Webster mice as previously described (22). Brain cortices were chopped and trypsinized for 10 min at 37°C. After trypsinization, 0.4 µg/ml trypsin inhibitor, 0.025% DNase, and 12 mM MgSO4 were added and mixed until tissue was thoroughly homogenized. Cells were then transferred to neurobasal medium containing B27 serum supplement, 1 mM glutamine, gentamicin, and Ara-C. Neurons were seeded on 50 µg/ml poly-D-lysine-coated 12-well tissue culture plates at a density of 2 x 106 cells.
Coimmunoprecipitations. Transfected COS7 cells were washed with phosphate-buffered saline (PBS) and lysed in buffer containing 50 mM Tris-HCl (pH 8.0), 0.15 M NaCl, 1% Nonidet P-40, phosphatase inhibitors (Sigma), and protease inhibitors (Roche). For immunoprecipitation, the lysates were incubated for 2 h at 4°C with the anti-HA antibody or an anti-6E10 antibody bound to protein G-Sepharose beads (Amersham Biosciences). The precipitates were then washed three times with lysis buffer and resuspended in sodium dodecyl sulfate (SDS) sample buffer. The samples were separated by SDS-polyacrylamide gel electrophoresis on 4 to 15% polyacrylamide gels, transferred electrophoretically to nitrocellulose membranes, and blocked with 5% nonfat dry milk. The blots were incubated with antibodies at room temperature for 1 h. Horseradish peroxidase-conjugated secondary antibodies were visualized by using an enhanced chemiluminescence detection system and exposed to film.
Biotin-labeled cell surface proteins. COS7 cells were transiently transfected with APP and ApoEr2 in Fugene 6 (Roche) according to the manufacturer's protocol and cultured for 24 h in Dulbecco modified Eagle medium containing 10% FBS. After 24 h, medium was changed to serum-free medium, and then F-spondin-containing medium was added. After 24 h, cells were washed twice with PBS, and surface proteins were labeled with sulfo-NHS-SS-biotin [sulfosuccinimidyl 2-(biotinamido)-ethyl-1,3-dithiopropionate)] [500 µl] at 500 µg/ml PBS (Pierce) under gentle shaking at 4°C for 30 min. Fifty microliters of quenching solution was added to cells, which were washed twice with Tris-buffered saline. Cells were lysed in 500 µl lysis buffer, collected with a cell scraper, disrupted by sonication on ice, incubated for 30 min on ice, and clarified by centrifugation (10,000 x g, 2 min). To isolate biotin-labeled proteins, lysate was added to immobilized NeutrAvidin gel (50 µl) and incubated at room temperature for 1 h. Gels were washed five times with wash buffer and incubated 1 h with SDS-polyacrylamide gel electrophoresis sample buffer including 50 mM dithiothreitol. Eluants were analyzed by immunoblotting.
Fe65-dependent APP luciferase transactivation assay. The Fe65-dependent APP luciferase transactivation assay was performed by the method of Cao and Sudhof (3, 15). HEK293 cells were cotransfected with the APP-Gal4 construct, Fe65-myc, and ApoEr2-HA, as well as the pG5E1B-luciferase reporter plasmid (to measure activation) and a ß-galactosidase plasmid (to normalize transfection efficiency). Luciferase activity from cell lysates was determined in triplicate using the luciferase assay kit (Promega) by VICTOR2 (Perkin-Elmer). Results were normalized to ß-galactosidase expression levels by using a ß-galactosidase enzyme assay kit (Promega).
Surgical procedures. For brain injections, adult male Sprague-Dawley rats (230 to 250 g; Taconic) were anesthetized with ketamine/xylazine and placed in a David Korf stereotaxic apparatus (David Korf Instruments, Tujunga, CA). Single-guide cannulae (33GA; Plastics One, Inc.) were implanted into the hippocampus (final coordinates relative to Bregma: anterior/posterior, –3.8 mm; medial/lateral, –2.2 mm; dorsal/ventral, –2.6 mm) by the method of Watson (32). Cannulae were secured to the skull with the aid of three stainless steel mounting screws and cranioplastic cement. After surgery, rats were allowed to recover for 6 days before the F-spondin treatment. F-spondin was administered at 4 µl daily for 7 days. Animals were sacrificed on day 8, and the hippocampus was collected. Tissue was homogenized in radioimmunoprecipitation assay buffer with phosphatase and protease inhibitors.
Statistical analyses. Experiments were repeated a minimum of four times unless otherwise noted. All data were analyzed by analysis of variance with Graphpad Prism 4 software, using Tukey's multiple-comparison test for posthoc analyses with significance determined at a P of <0.05. Descriptive statistics were calculated with StatView 4.1 and displayed as an expressed mean ± standard error of the mean.
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RESULTS |
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We then tested which part of the thrombospondin domain interacted with ApoEr2. The thrombospondin domain of F-spondin consists of six repeats. We generated constructs containing repeats 1 and 2, repeats 3 and 4, or repeats 5 and 6. Each thrombospondin construct was expressed with ApoEr2, immunoprecipitated with anti-c-myc antibody, and probed with anti-HA antibody. We found that the N-terminal thrombospondin repeats (1-4) interacted with ApoEr2, but repeats 5 and 6 did not (Fig. 1D). Again, the lack of coprecipitation of ApoEr2 with thrombospondin repeats 5 and 6 supports the specificity of these findings.
The ligand binding domain of ApoEr2 interacts with F-spondin. We examined which domains of ApoEr2 interacted with this thrombospondin fragment of F-spondin. We generated deletion constructs of ApoEr2 (Fig. 2A) altering expression of the ligand binding domain, the epidermal growth factor repeats (A and B), and the O-linked glycosylation domain. We cotransfected COS7 cells with the thrombospondin domain of F-spondin and these ApoEr2 deletion mutants. We found that constructs containing the entire ApoEr2 ligand binding domain immunoprecipitated with F-spondin (Fig. 2B) but that constructs lacking the ligand binding domain did not. We conclude that the ligand binding domain of ApoEr2, containing ligand binding domain repeats 3, 7, and 8, is required for the interaction of the thrombospondin domain of F-spondin (Fig. 2B).
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RAP inhibited ApoEr2 processing by F-spondin. To test whether the effects of F-spondin on ApoEr2 processing were due to binding of F-spondin to ApoEr2, we used an antagonist of the LDL receptor family, RAP (33). COS7 cells were transfected with ApoEr2, preincubated with 1 µM RAP, and treated with F-spondin-containing medium or control medium. As described above, we found that F-spondin treatment increased secreted ApoEr2 and ApoEr2 CTF. However, preincubation with RAP blocked F-spondin induction of secreted ApoEr2 and ApoEr2 CTF (Fig. 2D). These data suggest that the effects of F-spondin were mediated by interacting with ApoEr2.
We then asked whether F-spondin also affected endogenous ApoEr2 in neurons, using an antibody against the C-terminal fragment of ApoEr2. Primary neurons were treated with F-spondin-containing medium, and ApoEr2 CTF was measured in the cell lysates. We found that F-spondin treatment caused an increase in ApoEr2 CTF (Fig. 2E, top blot). We also injected F-spondin-containing medium into rat hippocampus to examine the effects of F-spondin in vivo. Again, we observed an increase in two ApoEr2 CTF (Fig. 2E, bottom blot).
APP interacts with the reelin and spondin domains of F-spondin. A recent study showed that F-spondin interacted with APP and inhibited ß-secretase cleavage (8), thus providing some insight into the mechanism of APP metabolism. We confirmed that APP interacts specifically with F-spondin, via the reeler and spondin domains, but not the thrombospondin domain (Fig. 3A). Thus, F-spondin interacted with both APP and ApoEr2 but through different domains. These data suggested that F-spondin could provide an extracellular link between APP and ApoEr2. We were concerned that transient cotransfection of APP with F-spondin in COS7 cells may have affected APP expression, but we found that the levels of APP were consistent (Fig. 3A, bottom blot).
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We then asked whether this interaction was increased by F-spondin. We coexpressed full-length APP with ApoEr2 and treated cells with media containing the single F-spondin domains (reelin, spondin, and thrombospondin) or media containing full-length F-spondin overnight. Interestingly, when cells were incubated with full-length F-spondin-containing medium, we observed increased coimmunoprecipitation of APP and ApoEr2 (Fig. 3C), but not when cells were incubated with any single F-spondin domain. Again, we were concerned that coexpression of APP and ApoEr2 in COS7 cells may affect their expression, so we determined the levels of APP and ApoEr2 in these cells. The levels of APP and ApoEr2 did not vary across conditions (Fig. 3C). Quantification of Western blots demonstrated that APP/ApoEr2 coprecipitation was increased by 105% after full-length F-spondin treatment (Fig. 3D), but no significant changes were observed after treatment with media containing the F-spondin fragments.
To test whether the interaction between APP and apoEr2 required full-length APP or only secreted APP, we coexpressed full-length APP with ApoEr2 and treated cells with media containing full-length F-spondin overnight. We immunoprecipitated APP with the C-terminal 369 antibody and probed with anti-HA antibody (for ApoEr2). We observed increased coimmunoprecipitation of APP and ApoEr2 after F-spondin treatment (Fig. 3E), demonstrating that full-length APP interacted with apoEr2.
F-spondin promotes APP and ApoEr2 cell surface levels and processing. We hypothesized that F-spondin bound the extracellular domains of APP and ApoEr2, clustering these molecules together and potentially affecting their presence on the cell surface. To measure cell surface expression of APP and ApoEr2, we coexpressed these molecules in COS7 cells and treated cells with control or F-spondin-containing medium for 12 h. Cell surface proteins were biotin labeled, isolated with avidin beads, and immunoblotted for ApoEr2 or APP. We observed that F-spondin treatment promoted cell surface levels of both APP and ApoEr2 (Fig. 4A). Expression of total cell-associated levels of ApoEr2 and APP were not altered after F-spondin treatment (Fig. 4A, bottom two blots).
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We then asked whether F-spondin also affected endogenous APP processing, using an antibody against the C terminus of APP. Primary neurons were treated with F-spondin-containing medium, and the levels of APP CTF in the cell lysates were measured. We found that F-spondin treatment increased in APP CTF (Fig. 5D, top blot), consistent with the increase in APP -CTF in transfected cells (Fig. 5A). We also injected control or F-spondin-containing media into rat hippocampus to examine the effects of F-spondin in vivo. We again observed an increase in APP CTF in this system (Fig. 5D, bottom blot).
Since F-spondin affected APP processing, we examined whether it affected Aß production. We found that F-spondin treatment decreased secreted Aß40 levels (by 70%) and Aß42 levels (by 50%) in COS7 cells (Fig. 6). We also tested whether F-spondin decreased Aß40 or Aß42 in primary neurons, as we had observed for the transfected COS7 cells. Exposure of cultured neurons to medium containing full-length F-spondin decreased the level of Aß by 70% compared to the level in cells treated with control medium (data not shown). These data are consistent with F-spondin reducing the level of APP ß-CTF.
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- and ß-CTF (C83 and C99), with ApoEr2. Surprisingly, we observed that these APP CTF also coprecipitated with ApoEr2 (Fig. 7). We were concerned that the interactions between ApoEr2 and APP CTF were not biologically relevant. For a negative control, we expressed APP and ApoEr2 in separate cells and, after their expression, mixed the cell lysates. ApoEr2 was immunoprecipitated with the anti-HA antibody, and the precipitate was probed with anti-c-myc antibody (recognizing APP). APP and ApoEr2 coimmunoprecipitated when they were coexpressed in the same cells, but not in separate cells (Fig. 7B).
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-secretase cleavage of APP CTF, the APP intracellular domain (AICD). We used an Fe65-dependent APP luciferase transactivation assay to assess AICD production in the presence of each domain of F-spondin or full-length F-spondin. HEK293 cells were cotransfected with APP-Gal4, Fe65, and ApoEr2 (3). Cells without Fe65 showed no response, as expected (3) (data not shown). As observed in the previous report (8), F-spondin resulted in 90% reduction of transactivation (Fig. 7C). Again, single domains of F-spondin did not affect production of APP fragments. |
DISCUSSION |
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Full-length F-spondin increases cleavage of ApoEr2, resulting in increased secreted ApoEr2 and increased ApoEr2 CTF (Fig.2C and D). These findings are consistent with our earlier studies that binding of apoE to the ligand binding domain of ApoEr2 led to increased extracellular metalloproteinase cleavage and intramembranous -secretase cleavage of ApoEr2 (10). These effects on cleavage may be related to increased transfer of intracellular pools of ApoEr2 to the cell surface after treatment with F-spondin (Fig. 4). Interestingly, the effect of F-spondin on ApoEr2 proteolysis depends on the presence of full-length protein and does not occur with only the thrombospondin domain that interacts with ApoEr2 (Fig. 2C). Thus, the effects of F-spondin on cleavage of apoE receptors may require the binding of F-spondin to other surface molecules, such as APP. This hypothesis is consistent with the effects of apoE receptor clustering for signal transduction in neurons (25).
In this work, we confirmed the report that F-spondin interacted with APP (8). The earlier study showed interaction via the spondin domain, although we found interactions with both the reelin and spondin domains (Fig. 3). Whichever domain interacts with APP in vivo, the current work suggests that a single F-spondin molecule could interact with both APP (via its N-terminal domains) and ApoEr2 (via its C-terminal domain). We immunoprecipitated ApoEr2 with APP both in transfected cells and in primary neurons, and this immunoprecipitation was increased by the presence of full-length (but not truncated) F-spondin. This experiment provides evidence that there could exist a tripartite complex of APP, F-spondin, and ApoEr2.
The interaction between F-spondin and APP in COS7 cells decreased ß-cleavage of APP (8). We confirmed these findings (Fig. 5A and B), using media containing F-spondin as opposed to coexpressing F-spondin in cells (8). The ß-cleavage of APP may be affected by the increased levels of APP on the cell surface after exposure to F-spondin (Fig. 4). We further demonstrated that this effect depended on full-length (not truncated) F-spondin and demonstrated that full-length F-spondin decreased secreted Aß levels (Fig. 6). Furthermore, we demonstrated that these effects on APP proteolysis depend on interactions with apoE receptors, since the inhibitor of the apoE receptor family, RAP, blocked the effects of F-spondin on APP proteolysis (Fig. 5B). This model is consistent with the results of several other studies that showed that APP physically interacted with another apoE receptor, LRP (14, 24), and that this interaction affected APP processing (13, 31).
In contrast to its effects on ß-cleavage of APP, F-spondin treatment increased the levels of -CTF of APP and CTF of ApoEr2 in transfected cells, in primary neurons, and in brain (Fig. 2, 3, and 5). These observations are in accordance with the effects of ligands binding to ApoEr2 (10). However, the dramatic increase in APP -CTF is in contrast to the reduction in AICD signaling after F-spondin treatment (8) (Fig. 7C), since AICD can be produced from -CTF. We hypothesize that the change in AICD signaling may not be due to a change in AICD levels, but in binding of Fe65 to AICD or a subsequent step in AICD signaling. Since F-spondin changes trafficking of APP (as evidenced by the increase of surface APP), it is possible that F-spondin could also affect the interaction of APP with cytoplasmic adaptor proteins.
We were surprised to find that in addition to the extracellular interaction between APP and ApoEr2 observed (which is increased in the presence of F-spondin), there is an intracellular interaction. Membrane-bound APP CTF (C99 and C83) with few extracellular amino acids still immunoprecipitated with ApoEr2 (Fig. 7A and B). Again, there is an analogous situation with APP and LRP, with the C-terminal domains of both proteins binding to different domains of the adaptor protein Fe65 (12, 21, 28), affecting processing of both LRP (7) and APP (21). It is possible that adaptor proteins, such as Fe65, could form an intracellular link between ApoEr2 and APP.
From these various experiments, we have developed a model of interaction of APP and ApoEr2 (Fig. 8). In this model, binding of APP and ApoEr2 to different domains of F-spondin clusters the transmembrane molecules together, allowing increased interaction of their C-terminal domains. These domains share adaptor proteins, such as JIP and disabled-1, potentially affecting signaling cascades mediated by these proteins. The potential clustering of APP and ApoEr2 leads to altered cleavage of each, both via extracellular metalloproteinases and intramembranous -secretase cleavage. The shared fates and functions of APP and apoE receptors suggest that apoE and other ligands of lipoprotein receptors could affect APP processing and thus influence Aß levels.
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ACKNOWLEDGMENTS |
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This work is supported by NIH grant AG14473.
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FOOTNOTES |
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