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NEUROPHARMACOLOGY
-Amyloid Peptide 1-42 on the Cytoprotective Action Mediated by 
7 Nicotinic Acetylcholine Receptors in Growth Factor-Deprived Differentiated PC-12 Cells
Department of Pharmacology and Toxicology, Alzheimer's Research Center, Medical College of Georgia, and the Veterans Affairs Medical Center, Augusta, Georgia
Received May 1, 2003; accepted July 29, 2003.
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Abstract |
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-amyloid peptide (A1-42)-containing senile plaques is a consistent finding in Alzheimer's disease (AD). However, the link between A1-42 and neuronal degeneration remains unclear. It has been reported that A peptides bind with selectivity to 
7 nicotinic acetylcholine receptors (7nAChRs) and that the two proteins are associated in human AD brain tissue. A potential functional interaction between 7nAChRs and A1-42 also has been suggested through the ability of nicotine to inhibit A1-42-induced cytotoxicity. Differentiated PC-12 cells share several features in common with cholinergic basal forebrain neurons. The cells express 7nAChRs, they require growth factor stimulation for their maintenance and survival, and nicotine protects against cytotoxicity subsequent to growth factor withdrawal. Using these cells as a model system, we designed experiments to more directly determine whether A peptides (A1-42 and A1-40) interfere with a potential nicotinic cytoprotective action and with the ability of nicotine to increase intracellular Ca2+. Differentiated PC-12 cells were preloaded with fura 2/acetoxymethyl ester and intracellular free Ca2+ levels were determined by fluorescent imaging. Nicotine-induced Ca2+ signals were inhibited by pretreatment with the 7nAChR-selective antagonists -bungarotoxin and methyllycaconitine, and they were completely absent in cells maintained in Ca2+-free medium. The nicotine response also was blocked by pretreatment with 100 nM A1-42. Nicotine (1-1000 µM) produced a concentration-dependent increase in cell viability in differentiated PC-12 cells that underwent nerve growth factor withdrawal for 24 h. Cell viability was maintained near 100% by 100 µM nicotine. The cytoprotective action of nicotine was efficiently antagonized by cotreatment with 7nAChR antagonists. A concentration-dependent inhibition of the cytoprotective action of nicotine also was produced by cotreatment with A1-42 (1-100 nM), but not with A40 -1. It is possible, therefore, that in AD, as growth factor support to basal forebrain cholinergic neurons declines, the interaction of A peptides with 7nAChRs may enhance toxicity by interfering with an important nicotinic signal for neuronal viability.
). Studies of the postmortem AD brain show that a decreased number of cholinergic cell bodies is present within the subcortical nucleus basalis of Meynert, origin of the basal forebrain cholinergic system (Whitehouse et al., 1982). Relative to many other areas of the brain, cholinergic forebrain neurons and their neuronal targets express relatively high numbers of nicotinic acetylcholine receptors (nAChRs). Ligand-binding studies have suggested two distinct types of functional nAChRs in human brain: one of these binds nicotine with high affinity, represented by the heteromeric 42 subtype, and the other binds -bungarotoxin with high affinity, mainly exemplified by the homomeric 7 subtype (for review, see Paterson and Nordberg, 2000). Compared with other potential subtypes, 7nAChRs exhibit a relatively high degree of selectivity for conducting Ca2+-mediated currents (PCa/PNa near 20) (Seguela et al., 1993). We and others have shown that the 7nAChR subtype may play an important role in nicotine's known cytoprotective actions (Donnelly-Roberts et al., 1996; Kaneko et al., 1997; Kihara et al., 1997; Carlson et al., 1998; Shimohama and Kihara, 1998; Dajas-Bailador et al., 2000; Jonnala and Buccafusco, 2001; Jonnala et al., 2003).
One factor that is applicable to basal forebrain cholinergic neurons is that they are dependent upon a constant supply of neurotropic substances for their maintenance and survival (Barde, 1989). In fact, nicotine and certain nAChR agonists can increase the levels of neurotrophic factors in the brain and increase the expression of NGF receptors (French et al., 1999; Jonnala et al., 2002). Differentiated PC-12 cells share with basal forebrain projection neurons their dependence on neural growth factors and their cholinergic phenotype. In fact, differentiation increases the cell surface expression of 7nAChRs 5-fold (Jonnala and Buccafusco, 2001). Thus, in addition to their widespread use as in vitro models of central neural cells, differentiated PC-12 cells constitute a relevant model for basal forebrain, 7nAChR-expressing cholinergic neurons.
The neurotoxic form of amyloid peptide, A1-42, can bind with high affinity to several cell surface proteins, including, receptors for advanced glycation end products and apolipoprotein E and, pertinent to this study, to 7nAChRs (Wang et al., 2000a,b). Because 7nAChRs are highly expressed on basal forebrain cholinergic neurons, the high-affinity binding of A1-42 to 7nAChRs may help target the neurotoxic properties of amyloid to forebrain projection neurons. Support for this concept is derived from the finding that A1-42 can be coprecipitated with 7nAChR protein from tissues derived from AD brain (Wang et al., 2000a). Also, nicotine-induced cytotoprotection seems to extend to cellular damage induced by toxic amyloid peptides (Martin et al., 1994; Zamani et al., 1997; Kihara et al., 1998; Shaw et al., 2002; Zanardi et al., 2002). Because blockade of 7nAChRs by amyloid peptides may result in the loss of a critical neurotrophic influence, a more direct test of this hypothesis might be to determine whether amyloid peptides can inhibit nicotine-induced cytoprotection. Differentiated PC-12 cells are well suited for these studies because removal of growth factors from the medium induces a time-dependent loss of cell viability that can be prevented by pretreatment with nicotinic, particularly 7nAChR, agonists. Also, cell surface 7nAChRs can be induced after exposure for several days with the 7nAChR antagonist methyllycaconitine (MLA) (Jonnala and Buccafusco, 2001). The mechanism by which 7nAChR agonists produce neuroprotection involves receptor- and calcium-dependent processes leading to the activation cell survival pathways, including the release of growth factors and the expression of cell surface TrkA receptors (Jonnala et al., 2002; Picciotto and Zoli, 2002).
The purpose of this study was to determine whether treatment of differentiated PC-12 cells with A1-42 could inhibit the cytoprotective actions of nicotine at doses of the peptide that were able to block the increase in intracellular Ca2+ produced by the agonist. We also sought to confirm the role of 7nAChRs in mediating both responses to nicotine.
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Materials and Methods |
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Cell Culture and Cell Viability Assay. Rat pheochromocytoma (PC-12) cells (American Type Culture Collection, Manassas, VA) were maintained in 150-cm2 tissue culture flasks in Dulbecco's modified Eagle's medium (DMEM) containing 7% horse serum, 7% fetal bovine serum, 1% nonessential amino acids, and 1% penicillin and streptomycin. The cells were incubated at 37°C in a 5% CO2-enriched, humidified atmosphere. To attain maximum differentiation, the cells were maintained in DMEM medium containing 50 ng/ml NGF (DMEM.NGF) for 7 days, with the medium being changed every 2 to 3 days. Cells were dissociated by trituration and plated at 10,000 cells/well on poly-L-lysine-coated 96-well plates containing DMEM.NGF media. Next, the differentiated cells were incubated with vehicle or with a test drug (prepared in serum-free DMEM media with no exogenous NGF) for the specified period of time. A parallel set of control cells were maintained in DMEM.NGF medium in each experiment. Cell viability (cytotoxicity) was determined by using the Cell Titer 96-cell proliferation/cytotoxicity assay kit (Promega, Madison, WI), which is based on the cellular conversion of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenltetrazolium bromide (MTT) into a formazan product that could be detected spectrophotometrically. At the completion of the incubation period, the culture medium was aspirated and 15 µl of dye solution in DMEM was added. After 4 h at 37°C, 100 µl of solubilization/stop solution was added, and the absorbance of solubilized MTT formazan products was measured at 579 nm. All data were normalized to untreated control cells in each plate.
Measurement of Intracellular Calcium. Differentiated PC12 cells were grown in 25-mm glass cover slip chambers previously coated with poly-L-lysine. Before Ca2+ imaging, the cells were washed once in Hanks' buffered saline consisting of the following: 150 mM NaCl, 10 mM Na HEPES, 10 mM D-glucose, 2.5 mM KCl, 2 mM MgCl2, 4 mM CaCl2 (pH 7.4). The cells were ester loaded with 3 µM fura 2/acetoxymethyl ester (Molecular Probes, Eugene, OR) in darkness at 37°C for 30 min. This was followed by rinsing three times with Hanks' buffered saline. Fluorescent images of fura 2-loaded PC-12 cells were captured with an Axiovert 135 fluorescent microscope (Carl Zeiss, Thornwood, NY) with PXL modular high-performance charge-coupled device camera. A visual field was selected containing 7 to 10 neurons. For excitation, a shutter was connected to the camera, permitting brief exposures of the neurons to the UV light. Changes in intracellular free Ca2+ ([Ca2+]i) were determined from the ratio of fura 2 fluorescence (510 nm) excited at 340 and 380 nm. Each data point represents the average values obtained from a total of 11 to 25 individual cells derived from three to four separate coverslip cultures per each experimental perturbation (except for the nine cells that contributed to the 500-µg dose of nicotine, which were derived from a single slide preparation). The [Ca2+]i was calculated according to the following equation: [Ca2+]i = Kd ((R - Rmin)/(Rmax - R))(Fmin380/Fmax380), where Kd is the dissociation constant derived from the interaction of Ca2+with the fluorescent dye, Rmin is the fluorescence ratio obtained in the absence of free Ca2+, Rmax is the fluorescence ratio obtained under saturating conditions, Fmin380 is the fluorescence level measured at 380 nm obtained in the absence of free Ca2+, and Fmax380 is the fluorescence measured at 380 nm under saturating conditions (Grynkiewicz et al., 1985). Kd was determined by using the fura-2 calcium imaging calibration kit (Molecular Probes), adjusted for 342 nM as per the experimental conditions. Responses to the highest concentration of nicotine (1000 µM) used in this study did not exceed the saturation potential of the dye because they were less than 20% of the Rmax.
Statistical Analysis. The data depicted in the text and figures will be presented as mean ± S.E.M. values. The existence of a significant difference between or among experimental groups was determined by analysis of variance using the raw data. Post hoc analysis was performed by using an orthogonal contrasts t test. The criterion for statistical significance was P < 0.05 (two-tailed) for all comparisons.
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7nAChRs (Bmax) measured in undifferentiated cells was shown to be increased 5-fold in NGF-differentiated cells (Jonnala and Buccafusco, 2001). Cell death was induced by replacing the normal medium with serum-free medium and eliminating the exogenous NGF. These conditions were maintained for 24 h at which time mitochondrial integrity was assessed via the MTT assay. Growth factor withdrawal decreased cell viability by about 35% (Fig. 1, top). Incubation with nicotine (initiated at the time of growth factor withdrawal and maintained during the 24-h withdrawal period) produced a concentration-dependent reversal in the growth factor withdrawal-induced loss of cell viability that reached maximal with 100 µM (F5,68 = 358.8, P < 0.0001). The effect of nicotine was so complete as to provide cell viability values near levels associated with growth factor-maintained cells (Table 1). As a preliminary experiment to the subsequent experiments with A1-42, the peptide was introduced into the cell medium at the time of growth factor withdrawal (and maintained during the 24-h withdrawal period) to determine any direct effect on cell viability. These data are shown in Fig. 1 (bottom). A1-42 produced a concentration decrement in cell viability that was significant after administration of the 10, 100, and 1000 nM concentrations (F5,17 = 542.9, P < 0.0001). The decrement in cell viability after 10 and 100 nM A1-42 amounted to only a 4.7 and a 5.5% change, respectively, relative to untreated, growth factor-withdrawn cells (in contrast, 100 nM A1-42 produced no effect on cell viability in growth factor-maintained cells; Table 1). Although the effect of these two concentrations were statistically significant (very low error values), only 1000 nM A1-42 produced a substantial loss in cell viability (22.4%). Therefore, the 1000 nM concentration was not used in subsequent experiments.
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Calculation of resting [Ca2+]i in differentiated PC-12 cells (49.6 ± 2.8 nM) was within the normal physiological range as reported previously for cultured PC-12 cells (Gueorguiev et al., 1999). Acute exposure to nicotine resulted in a concentration-dependent increase in [Ca2+]i of up to almost 5-fold the resting level (F3,897 = 55.8, P < 0.0001). The change in [Ca2+]i was transient, peaking within 20 s after application, and returning to resting levels within 60 s (Fig. 2, top). These findings were similar to those reported previously in nondifferentiated PC-12 cells (Gueorguiev et al., 2000). In Ca2+-free media (Fig. 2, bottom), nicotine, even at the highest concentration (1000 µM), produced no change in [Ca2+]i (F2,914 = 206.7, P < 0.0001; t = 20.3, P < 0.0001). Moreover, pretreatment (30 min earlier) with the 7nAChR-selective antagonist -bungarotoxin (the pretreatment was necessary to account for the slow binding kinetics of the toxin) significantly blocked the nicotine-induced increase in [Ca2+]i (t = 9.1, P < 0.0001). There was a small, but significant [Ca2+]i signal (relative to the response in Ca2+-free media) remaining in the cells treated with -bungarotoxin and nicotine (t = 8.0, P < 0.0001).
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As with the intracellular Ca2+ data, pretreatment with -bungarotoxin significantly blocked the nicotine-induced increase in cell viability in growth factor withdrawn cells. In fact, very low concentrations (10 nM) of either -bungarotoxin or the 7nAChR-selective antagonist MLA essentially eliminated (F5,103 = 460.0, P < 0.0001) nicotine's cytoprotective action (Fig. 3). In the next series, we compared the ability of amyloid peptide (A1-42) with MLA to inhibit the increase in [Ca2+]i in differentiated PC-12 cells. Both drugs were administered into the media 30 min before the addition of 100 µM nicotine (Fig. 4). Each of the pretreatments significantly suppressed the nicotine-induced increase in [Ca2+]i (F2.962 = 316.9, P < 0.0001).
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In the final series, we compared the ability of two amyloid peptides, A1-42 and A1-40, to inhibit nicotine-induced cytoprotection. (Although the 1-40 peptide is shorter by two residues than the 1-42 peptide, both the cytotoxic sequence and the 7nAChR binding sequence are within amino acids 1-40). The reverse peptide A40 -1 also was evaluated to provide an additional control. The pretreatment drugs were coadministered with 100 µM nicotine. Each cotreatment-nicotine regimen was maintained during the 24-h growth factor withdrawal period. Growth factor withdrawal reduced cell viability to 66.6 ± 1.8% relative to growth factor-maintained control cells (Fig. 5). Treatment with 100 nM A1-42 (in the absence of nicotine) enhanced growth factor withdrawal-induced cell death significantly (t = 2.29, P = 0.024), but only by 5.2% (Fig. 1, bottom). Neither A1-40 nor the reverse peptide A40 -1 enhanced cell death (P > 0.10). However, cotreatment of A1-42 with nicotine resulted in a concentration-dependent inhibition of the cytoprotective effect of nicotine (F9,98 = 361.6, P < 0.0001), with 10 nM (t = 4.72, P < 0.0001) and 100 nM (t = 22.5, P < 0.0001) maintaining highly significant decrements in cell viability relative to nicotine-treated controls. As such, the peptide was as effective as -bungarotoxin or MLA in preventing nicotine-induced cytoprotection (Fig. 3). Likewise, cotreatment with A1-40 significantly blocked the protective effect of nicotine (t = 31.2, P < 0.0001). In contrast, copretreatment with the reverse peptide A40 -1 was without significant effect on nicotine-induced cytoprotection (t = 1.65, P = 0.10).
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), although more recent studies have disputed a beneficial action of smoking as related to AD (Brenner et al., 1993; Ott et al., 1998). If the potential neuroprotective effect of smoking tobacco is related to the consumption of nicotine, then it is not clear why the drug is less protective in AD than it is in Parkinson's disease. An answer to this question may reside in the recent finding that the neurotoxic form of amyloid peptide, A1-42, can bind with high affinity to the 7 subtype of the nAChR (Wang et al., 2000a,b). Because 7nAChRs are expressed on basal forebrain cholinergic neurons that project to the hippocampus and cortex, the high-affinity binding of A1-42 to 7nAChR may help target the neurotoxic properties of amyloid to forebrain projection neurons. Whereas nicotine has been shown to offer protection against the cytotoxicity induced by amyloid peptides (see Introduction), the results of this study support the hypothesis more directly by demonstrating that a slightly cytotoxic concentration of A1-42 prevents the cytoprotective actions of nicotine. One of the concentrations of A1-42 (100 nM) that prevented the cytoprotective action of nicotine also blocked the ability of the drug to induce an acute increase in intracellular free Ca2+ in the same cells. This concentration of A1-42 is not grossly out of line with the levels of A protein measured in cerebrospinal fluid (about 4 nM) derived from AD patients (Nakamura et al., 1994), particularly because interstitial levels of the protein are likely to be greater nearby plaque deposition. In fact, the more reasonable 10 nM concentration of the peptide was slightly cytotoxic (Figs. 1 and 5), and it also significantly inhibited the cytoprotective effect of nicotine. The selectivity of action of A1-42, both with respect to its slight cytotoxicity and with respect to its ability to block the cytoprotective action of nicotine, was inferred from the lack of effect in both situations of the reverse peptide A40 -1. The finding that A1-40 was about as effective as A1-42 confirms the earlier observation that both the cytotoxic sequence and the 7nAChR binding sequence are within amino acids 1-40 (Harkany et al., 1999; Wang et al., 2000b). The observation that the cytoprotective responses to nicotine and the ability of the drug to increase [Ca2+]i were almost abolished after treatment with selective 7nAChR antagonists suggest that the effects produced by A1-42 in this study were mediated by 7nAChRs. Although the participation of other subtypes of nAChRs cannot be ruled out, the role of 7nAChRs in the cytoprotective action of nicotine is consistent with our previous studies that examined the effects of subtype selective agonists and antagonists (Jonnala and Buccafusco, 2001) and by using the 7nAChR agonists choline and pyrrolidinecholine (Jonnala et al., 2003).
In a direct corollary to the in vitro studies of nicotine-amyloid interactions, it has been reported that nicotine inhibits the expression of A-induced amnestic responses as measured by using several behavioral techniques in mice (Maurice et al., 1996). It has yet to be determined whether the behavioral responses assessed in the study were mediated by 7nAChRs. Again the reverse situation has not yet been evaluated, i.e., whether A pretreatment inhibits nicotine-induced positive cognitive responses. Recent preliminary studies in this laboratory, however, have indicated that intracerebroventricular injection of A1-42 prevents the hypertensive response to central administration of choline, a selective and full agonist for the 7nAChR (Li and Buccafusco, 2002).
The mechanism by which nicotine induces its neuroprotective action initially requires extracellular Ca2+ (Dajas-Bailador et al., 2000; Picciotto and Zoli, 2002). This finding seems to be at odds with the known calcium-mediated excitotoxicity induced by glutamate agonists such as NMDA. Although both receptors admit Ca2+, the increases in [Ca2+]i induced by NMDA are much greater in magnitude than those induced by nicotine. Also, the intracellular accumulation of 45Ca2+ produced by longer exposure times to NMDA was not reproduced by nicotine (Dajas-Bailador et al., 2000). Thus nicotine may activate mechanisms that buffer increases in intracellular Ca2+ more efficiently than NMDA. Alternatively, nicotine may activate anti-apoptotic pathways, e.g., involving Janus kinase 2 (Shaw et al., 2002); and the drug has been shown to increase growth factor signaling either by increasing the growth factor levels (Picciotto and Zoli, 2002) or by increasing the expression of growth factor receptors (Terry and Clarke, 1994; Jonnala et al., 2002). Because each of these pathways begin with increases in extracellular Ca2+, our finding that A1-42 blocks this crucial event (as well as the cytoprotective action of nicotine) supports the possibility that high levels of brain A may interfere with an important nicotinic signal for neuronal viability.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: 7nAChR, 7 nicotinic acetylcholine receptor; NGF, nerve growth factor; MLA, methyllycaconitine; DMEM, Dulbecco's modified Eagle's medium; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenltetrazolium bromide; [Ca2+]i, intracellular calcium concentration; NMDA, N-methyl-D-aspartate.
Address correspondence to: Dr. Jerry J. Buccafusco, Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912-2300. E-mail: jbuccafu{at}mail.mcg.edu
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