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(The FASEB Journal. 1999;13:63-68.)
© 1999 FASEB

Research Communications

TNF{alpha} plus IFN{gamma} induce the production of Alzheimer ß-amyloid peptides and decrease the secretion of APPs

I. Blaskoa, F. Marxa, E. Steinerb, T. Hartmannc and B. Grubeck-Loebensteina,1

a Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria
b Department of Surgery, `Bezirkskrankenhaus' Hall, Austria
c Center for Molecular Biology Heidelberg (ZMBH), University of Heidelberg, Heidelberg, Germany


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The appearance of inflammatory markers associated with amyloid plaques indicates a state of chronic inflammation in Alzheimer's disease (AD). Multiple epidemiological studies also suggest that patients taking anti-inflammatory drugs have a decreased risk of developing AD. Here we present evidence that inflammatory cytokines can alter the metabolism of the ß-amyloid precursor protein (ßAPP). We show that the combination of tumor necrosis factor {alpha} and interferon {gamma} triggers the production of ß-amyloid peptides and inhibits the secretion of soluble APPs by human neuronal and extraneuronal cells. The results demonstrate a new mechanism by which inflammatory components can exacerbate the fundamental pathology in AD.—Blasko, I., Marx, F., Steiner, E., Hartmann, T., Grubeck-Loebenstein, B. TNF{alpha} plus IFN{gamma} induce the production of Alzheimer ß-amyloid peptides and decrease the secretion of APPs. FASEB J. 13, 63–68 (1999)


Key Words: tumor necrosis factor {alpha} • interferon {gamma} • ßAPP • amyloid beta • Alzheimer's disease • glycosylation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A DEFINING HISTOPATHOLOGICAL feature of Alzheimer's disease (AD)2 is the presence of diffuse and neuritic plaques localized to specific brain regions, particularly the temporal lobe. The principal constituent of these extracellular deposits is the 39–43 amino acid ß-amyloid peptide (Aß), which is derived by proteolytic processing from the ß-amyloid precursor protein (ßAPP). It is now well established that Aß is released from ßAPP through cleavage by yet unidentified proteases referred to as ß and {gamma} secretase (1). Cleavage occurs primarily after residue 40 of Aß [Aß (1–40)], and occasionally after residue 42 [Aß (1–42)]. Whereas intracellular Aß (1–40) is produced in the late trans-Golgi network or in endosomes, the endoplasmic reticulum seems to be a main site of Aß (1–42) generation (2, 3). Aß can be toxic in vitro (4) and in vivo (5). Although there is still substantial debate about when Aß becomes involved in AD, accumulating evidence now points to an early and sometimes causative role in the pathogenic cascade (6). In addition to the amyloidogenic pathway for ßAPP metabolism, full-length ßAPP molecules can also be proteolyzed by an enzyme termed {alpha}-secretase, which cleaves ßAPP within its Aß region, releasing a soluble fragment (soluble amyloid precursor protein, or APPs) from the extracellular domain. APP secretion depends on the stage of glycosylation of full-length ßAPP (7). Neuroprotective and growth-promoting properties have been attributed to APPs (8). As Aß is toxic but APPs is protective, the predominance of the one or the other metabolic pathway seems decisive for the development of Aß pathology and the progression of the disease.

Cytokines have been shown to influence the production of ßAPP (9, 10). This is of interest, as inflammatory substances are associated with Aß plaques and antiinflammatory drugs have been shown to lower the risk of developing AD (11). Published work has demonstrated that aggregated Aß can trigger the release of cytokines from monocytic cells (12). Complement components have also been shown to bind to Aß and increase its cytotoxicity (13). C1q binding to Aß may also be a trigger mechanism for the activation of the classical complement cascade (14). These earlier studies concentrated on the interaction of preformed Aß with the immune system. The molecular mechanism linking inflammation to Aß production in AD remains yet elusive. We report here that tumor necrosis factor {alpha} (TNF{alpha}) in combination with interferon {gamma} (IFN{gamma}) induces the production of Aß and inhibits APPs secretion.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cells and cytokines
The neuroblastoma cell line Sk-n-sh was purchased from the American Type Culture Collection (Rockville, Md.). Human thyroid tissue was obtained as a by-product of thyroidectomy. Thyroid epithelial cells (TEC) were purified and cultured as previously described (15). Human recombinant IFN{gamma} (specific activity, 3 x 107 IU/mg) and TNF{alpha} (specific activity, 5 x 107 IU/mg) were a gift from Bender & Co., Vienna, Austria. Cells were incubated with or without cytokines in MEME and RPMI 1640, 5% fetal calf serum (Life Technologies, Vienna, Austria) for 1–7 days at 37°C, 5% CO2.

Antibodies
For detection of full-length ßAPP and APPs, the monoclonal antibody (mAb) 22C11 (Boehringer, Germany) was used. This antibody specifically binds to the amino terminus of ßAPP. The following antibodies were used to detect Aß ( Fig. 1) : R1282 (16), W02 binding to amino acids (aa) 1–16 of Aß (17), G2–10 binding to aa 33–40 of Aß, and G2–11 binding to aa 35–42 of Aß (17). For the detection of 22C11 mAb by Western blotting, a secondary antibody linked with horseradish peroxidase (Amersham, Vienna, Austria) was used.



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  		Figure 1. Schematic representation of the binding site of specific antibodies to ßAPP; Aß (1–42).

Metabolic labeling and immunoprecipitation
Cells were washed and incubated in methionine-cysteine free medium. Thereafter, they were subjected for 6 h to metabolic labeling with 280 µCi/ml L-[35S] cysteine and L-[35S] methionine (Amersham) in the absence or presence of cytokines. Media were then collected and cells were harvested. Cells were lysed in phosphate-buffered saline (PBS), containing 1% Triton-X-100, 1 mg/ml bovine serum albumin, and the protease inhibitors aprotinin, pepstatin, and leupeptin (Sigma, Vienna, Austria). The supernatants and cell lysates were then analyzed by immunoprecipitation. They were first preabsorbed with protein G-agarose (Sigma) and centrifuged. Then antibodies to ßAPP or Aß were added and the mixture was incubated overnight. Antigen-antibody complexes were then absorbed by protein G-agarose by shaking at 4°C for 45 min, centrifuged, washed, heated to 90°C for 10 min, and separated on 10 or 16% Tris-Tricine gels. After electrophoresis, the gels were fixed and incubated for 20 min in Amplify (Amersham). Finally, gels were dried between cellulose sheets (Gel-dryer, Bio-Rad, Vienna, Austria) and exposed to an X-ray film (Amersham) for 4–14 days at -20°C.

Western blotting
Protein extracts were heated in sodium dodecyl sulfate (SDS) lysis buffer after the addition of ß-mercaptoethanol. Identical amounts of proteins were applied to 10% PAA-SDS gels. After electrophoretic transfer, nitrocellulose filters were blocked and incubated with the primary antibodies. Secondary antibodies were labeled with horseradish peroxidase. Protein bands were visualized with a chemiluminescent substrate detection system (Pierce, Rockford, Ill.) and evaluated densitometrically with a Scanpack system (Biometra, Göttingen, Germany).

Northern blotting
For Northern blotting, total RNA was prepared by TRI-zol reagents (Life Technologies). RNA was denatured, fractionated on formaldehyde/agarose gels, and transferred to nylon filters. Probes for APP695 and GAPDH were generated and labeled with Digoxigenin-11-dUTP (Boehringer Mannheim, Mannheim, Germany) by polymerase chain reaction (PCR) using sequence specific primers; ßAPP: 5'-CCGTGGAGCTCCTCCCCGTG-3' and 5'-TAGCCGTTCTGCTGCATCTTG-3'; GAPDH: 5'-CCATGGAGAAGGCTGGGG-3' and 5-' CAAAGTTGTCATGGATGACC-3'). Hybridization and detection were performed with the DIG luminescence detection kit (Boehringer Mannheim) according to the manufacturer's protocol.

PCR
For reverse transcriptase (RT) -PCR, 2 µg of total RNA were reverse transcribed with the system A3500 (Promega, Madison, Wis.) using oligo(deoxythymidine) priming. Primers and experimental conditions were the same as previously described (18). The primer sets used identified the main ßAPP isoforms: ßAPP 695, ßAPP 751, and ßAPP 770.

Assessment of apoptosis
After washing in PBS, cells were gently resuspended in 200 µl propidium iodide (0.005%, PI, Sigma) together with Triton X-100 (0.1%, Sigma) and incubated at room temperature for 30 min. The PI fluorescence of individual nuclei was measured using a FACScan flow cytometer (program Lysis II, Becton Dickinson, Mountain View, Calif.), as described previously (19, 20). Red fluorescence due to PI staining of DNA was expressed on a logarithmic scale and the forward scatter of particles was measured simultaneously. 5000 events were measured on the scatter gate. All measurements were performed under identical instrumental settings. This technique identified a population of apoptotic nuclei that had lower fluorescence intensity than diploid nuclei, but was clearly distinct from debris and nonviable cells. The number of apoptotic nuclei was expressed as percentage of the total number of events.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
TNF{alpha} plus IFN{gamma} stimulate the production of ßAPP and induce the generation of ß-amyloid peptides in Sk-n-sh neuroblastoma cells
One cytokine whose role in neuropathology is not yet understood is TNF{alpha} (8, 21). Whereas several studies suggest that TNF{alpha} can promote neuronal damage and increase the severity of diseases of the central nervous system (22, 23), others claim it may have a protective effect (24). TNF{alpha} synergizes with IFN{gamma} in a number of activities (25). We therefore examined the effect of TNF{alpha} on its own as well as that of a combination of TNF{alpha} and IFN{gamma} on the production and metabolism of ßAPP in neuroblastoma cells. After 24 h of incubation, neither the amount of specific mRNA nor the production of ßAPP protein or its metabolites were influenced by TNF{alpha} at concentrations from 10 to 1000 U/ml (not shown). Neither did IFN{gamma} on its own affect ßAPP production. A combination of TNF{alpha} and IFN{gamma} did, however, induce an increase in ßAPP mRNA ( Fig. 2A). At the same time, ßAPP protein synthesis was enhanced. This was accompanied by an increase in ßAPPs metabolism. APPs production was stimulated and a 3 to 4 kDa double band corresponding to Aß and p3 became visible after metabolic labeling and immunoprecipitation of conditioned supernatants with the Aß specific antibody R1282. The p3 band was hereby more pronounced than the Aß one. The effect was observed from a dose of 10 U/ml of each cytokine upward, but was most pronounced when 1000 U of TNF{alpha} and 500 U of IFN{gamma}/ml were used. The same result was obtained when other Aß-specific antibodies—namely, W02 (Aß; 17), G2–10 (Aß40 and p3/40; 17), or G2–11 (Aß42 and p3/42; 17)—were used ( Fig. 2B). As the mAb G2–10 is specific for Aß (1–40) but G2–11 for Aß (1–42), both amyloid peptide forms were being produced. Detection of an Aß band with the mAb W02 also demonstrated the presence of fragments containing the full amino terminus.





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  		Figure 2. Effect of TNF{alpha} and IFN{gamma} on the production and metabolism of ßAPP in the Sk-n-sh human neuroblastoma cell line (A, B) and human thyroid epithelial cells in primary culture (C ) after 24 h incubation. Cells were either untreated or treated with IFN{gamma} (500 U/ml), TNF{alpha} (1000 U/ml), or a combination of both cytokines at the concentrations indicated. ßAPP-mRNA was assessed by Northern blotting, ßAPP and APPs by Western blotting, using the mAb 22C11. For the detection of amyloid ß peptides, cells were subjected to metabolic labeling. Conditioned media were immunoprecipitated with antibodies specific for Aß, R1282 (A, C), G2–10, G2–11, and W02 (B). The proteins were then subjected to 16% Tris-Tricine gel electrophoresis.

TNF{alpha} plus IFN{gamma} stimulate the generation of ß-amyloid peptides in human primary cells
Based on the observation that the combination of TNF{alpha} and IFN{gamma} induced the production of Aß peptides in Sk-n-sh cells, we examined primary cultures of human TEC. This highly differentiated cell type represents a valuable model for studies of ßAPP metabolism, as TEC produce large amounts of the glycosylated holoprotein as well as its metabolites (18). TEC were unaffected by TNF{alpha} or IFN{gamma} alone, but were influenced by the combination of both cytokines ( Fig. 2C). Whereas the effects of TNF{alpha} and IFN{gamma} on ßAPP holoprotein and APPs were less pronounced than in the neuroblastoma cell line, a 3 kDa/4 kDa double band corresponding to ß-amyloid peptides was clearly visible after immunoprecipitation of supernatants conditioned by cytokine-treated cells. As in neuroblastoma cells, the 3 kDa band was the dominant one after 24 h of incubation. Although the number of cells available from thyroid tissue samples was not sufficiently high to perform mRNA analysis, it seems likely that the same stimulatory mechanism as in Sk-n-sh cells was operative in TEC. The results demonstrate for the first time that cytokines can trigger the production of amyloidogenic peptides in primary human cells.

Secretion of ß-amyloid peptides does not result from cell damage due to cytokine treatment
Recent work indicates that apoptosis is associated with a significant increase of metabolic products derived from ß-secretase cleavage and suggests that an overproduction of Aß may be the consequence of cellular damage from various causes (26). Staining of nuclear DNA with PI iodide demonstrated the appearance of an apoptotic population after cytokine treatment in neuroblastoma, but not in primary cells ( Table 1). As the two cell types did not differ in their production of amyloidogenic metabolites, this result makes a causal relationship between the occurrence of apoptosis and the changes in ßAPP metabolism unlikely.


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  		Table 1. TNF{alpha} (1000 U/ml) + IFN{gamma} (500 U/ml) induce apoptosis in neuroblastoma but not in primary cellsa

Prolonged cytokine treatment inhibits ßAPP maturation and secretion, but Aß production is sustained
Neuroblastoma and primary cells were maintained in culture for up to 7 days in the absence or presence of cytokines. From day 3 onward, striking changes in ßAPP metabolism were noted ( Fig. 3). The 145 kDa band, which most likely is fully glycosylated ßAPP, disappeared in cells treated with TNF{alpha} and IFN{gamma}, whereas the intensity of the 115 kDa band corresponding most likely to immature ßAPP increased ( Fig. 3A, D, F). In thyroid cells, a double band was characteristically visible in the 115 kDa domain ( Fig. 3D). The lower of the two bands, which most likely corresponds to a ßAPP variant with a low degree of glycosylation, increased in intensity upon cytokine treatment. This feature was also visible in cells treated with IFN{gamma} only, but was more pronounced when the combination of TNF{alpha} and IFN{gamma} was used. Decreased ßAPP maturation was accompanied by a decrease in APPs secretion. In contrast, the production of Aß peptides was not reduced ( Fig. 3A, D, E). Aß bands were detectable in both cell types when conditioned supernatants of cytokine-treated cells were immunoprecipitated with the antibody R1282 ( Fig. 3A, D). The 4 kDa band was the dominant one after 72 h and more of incubation. Single bands in the 4 kDa domain became visible when the supernatants of cytokine-treated cells were immunoprecipitated with the antibodies G2–10 and G2–11 ( Fig. 3E). Under identical experimental settings, the Aß (1–42) band was almost as strong in intensity as the Aß (1–40) one. ßAPPmRNA and ßAPP isoform expression were unchanged after prolonged cytokine treatment ( Fig. 3B, C).



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  		Figure 3. Late effects of TNF{alpha} and IFN{gamma} on the production and metabolism of ßAPP in Sk-n-sh cells and human thyroid epithelial cells in primary culture. Cells were cultured for 72 h in the absence of stimuli or in the presence of IFN{gamma} (500 U/ml), TNF{alpha} (1000 U/ml), or a combination of both cytokines at the concentrations indicated. ßAPP, ßAPPmRNA, APPs, and Aß peptides were assessed as described in Fig. 2. A–C) Neuroblastoma cells; D–F) thyroid cells. B) A representative experiment on ßAPPmRNA in Sk-n-sh cells. C) A representative experiment on ßAPP isoform analysis in Sk-n-sh cells by RT-PCR, as described in Material and Methods. F) Changes in the production of ßAPP and APPs in thyroid cells in response to cytokine treatment. Values were obtained by densitometric scanning of Western blots and represent relative changes in percent compared to untreated controls, which were considered as 100%, ±SEM (n=4).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The central role of Aß in AD pathogenesis, together with the indication that anti-inflammatory therapy may prevent AD (27), suggests that one mechanism of action of cytokines in the brain might be to modulate Aß generation. Although it is still not entirely clear whether antiphlogistic drugs work through inflammatory cells in AD, recent work demonstrating that chronic use of nonsteroidal inflammatory medication is associated with decreased microglial activation still strongly favors this possibility (28). The data reported here demonstrate that the combination of TNF{alpha} and IFN{gamma} can trigger the production of Aß peptides by human cells, revealing an attractive mechanism how inflammatory factors can accelerate the development of AD.

The biological basis for the regulation of Aß formation by cytokines seems complex, as at least two modes of actions are operative in our system. First ßAPP production is transcriptionally stimulated, leading to an increase in ßAPP metabolism ( Fig. 2). Augmented APPs secretion is hereby accompanied by the appearance of Aß peptides in the culture medium. Production of these peptides could be the result of internalization of ßAPP holoprotein from the cell surface into the late endosome compartment (29). The relative abundance of p3 over Aß at this early time point supports this concept, as it suggests {alpha}-secretase activity. Although ßAPP expression levels are generally normal in AD brain, cytokines might still trigger a minor increase in ßAPP expression locally. Stimulation of ßAPP production and its metabolic consequences could only be induced by a combination of TNF{alpha} and IFN{gamma}, not by either mediator on its own. This demonstrates that multiple signals with a degree of cell and tissue specificity are necessary for regulation of the expression and degradation of ßAPP.

At a later time point, a second regulatory mechanism was observed ( Fig. 3). From day 3 onward, ßAPP maturation and APPs secretion were suppressed in cytokine-treated cells, whereas the production of Aß peptides was maintained. The effect was also achieved by IFN{gamma} alone, but was more pronounced when TNF{alpha} was also present. The predominance of low molecular weight ßAPP in combination with the almost complete loss of higher molecular weight variants indicates incomplete glycosylation. This suggests that prolonged exposure of cells to cytokines leads to the retention of immature ßAPP in the endoplasmic reticulum. This could be due to an altered metabolism of chaperones such as presenilin (30) in the presence of cytokines. Studies are presently under way in our laboratory to clarify this possibility. Defect maturation of ßAPP has been shown to affect its sorting rates and may lead to a decreased secretion of APPs (7, 31).

In summary, we provide evidence that the combination of TNF{alpha} and IFN{gamma} can induce the production of Aß peptides in neuroblastoma cells as well as in nonneuronal cells in primary culture. The data outline a novel molecular mechanism for how inflammation may be linked to Aß production in AD. As there is still no evidence that inflammation could precede Aß production, it seems likely that cytokine effects are no initial event, but may rather represent an enhancer mechanism. Cytokines might thus play a feedback role in a vicious cycle of ßAPP metabolism, Aß production and the pathogenesis of AD. The synergy of mediators necessary to induce maximal effects may, however, limit the circumstances in which inappropriate ßAPP processing takes place.


   ACKNOWLEDGMENTS
 
We thank D. Selkoe for providing antibodies. We are grateful to G. Wick for his continuous support and to G. Adolf (Bender & Co, Vienna, Austria) for kindly providing TNF{alpha} and IFN{gamma}. We are also grateful to R. Fuchs for stimulating discussions. This work was supported by The Austrian Science Funds, grant P12440-MED.


   FOOTNOTES
 
1 Correspondence: Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck. E-mail: Beatrix.Grubeck{at}oeaw.ac.at

2 Abbreviations: aa, amino acids; Aß, ß-amyloid peptide; AD, Alzheimer's disease; APPs, soluble amyloid precursor protein; ßAPP, ß-amyloid precursor protein; TNF, tumor necrosis factor; IFN, interferon; TEC, thyroid epithelial cells; mAb, monoclonal antibody; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; PCR, polymerase chain reaction; RT, reverse transcriptase; PI, propidium iodide.

Received for publication July 14, 1998. Revision received September 19, 1998.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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