Amyloid precursor protein (APP) ()can be degraded by several different pathways. One pathway releases A, a 39-43-amino acid peptide that is the main constituent of the amyloid plaques in the brains of Alzheimer's disease (AD) patients (Glenner and Wong, 1984; Masters et al., 1985). The C-terminal cleavage of A, termed -secretase cleavage, occurs in the putative transmembrane domain by an unknown mechanism (Kang et al., 1987). The N-terminal cleavage, -secretase, releases a soluble N-terminal derivative that is found in human cerebrospinal fluid (Seubert et al., 1993). Another pathway, termed the -secretase pathway, cleaves within the A segment to release APP, a nonamyloidogenic soluble N-terminal derivative, also found in human cerebrospinal fluid (Esch et al., 1990; Palmert et al., 1992). The exact cleavage site is between residues 16 and 17 of A (Anderson et al., 1991; Wang et al., 1991). The soluble APP derivative found in the conditioned media of the cell line used in this study, HEK 293 cells, is almost exclusively the result of -secretase cleavage (Wang et al., 1991).

Modulation of APP levels may be of physiological consequence. APP induces a 2-fold increase in the phosphorylation of tau, a microtubule-associated protein that is hyperphosphorylated in AD (Greenburg et al., 1994). In addition, APP has a trophic effect on cerebral neurons in culture (Araki et al., 1991) and is mitogenic for Swiss 3T3 cells (Schubert et al., 1989). APP must be added to the growth medium of two different cell lines with reduced APP production to restore normal cell proliferation (LeBlanc et al., 1992; Ninomiya et al., 1993). APP also protects neurons against hypoglycemic damage and glutamate toxicity, causing a rapid and prolonged reduction in intracellular Ca concentration (Mattson et al., 1993).

Production of APP has been found to be influenced by several agents. Augmented iron, phorbol 12,13-dibutyrate, interleukin 1, cholinergic agonists, estrogen, cholinesterase inhibitors, and cellular depolarization all increase -secretase cleavage (Bodovitz et al., 1995; Buxbaum et al., 1992; Caporaso et al., 1992a; Gillespie et al., 1992; Jaffe et al., 1994; Nitsch et al., 1993). Decreases in -secretase cleavage have been observed with the iron chelator desferrioxamine (Bodovitz et al., 1995) as well as agents of a less modulatory and more disruptive manner, such as monensin (disruption of distal Golgi cisternae), methylamine (alkalization of acidic intracellular compartments), and site-directed mutagenesis (Caporaso et al., 1992b; Sisodia, 1992; De Strooper et al., 1993; Usami et al., 1993).

In this study, we have examined the possible disruptive effects of elevated cholesterol on APP processing. Increases in cholesterol previously have been shown to modify the function of certain membrane proteins. Function has decreased, as in the case of the Meta I-Meta II transition of rhodopsin (Mitchell et al., 1990), or increased, as in the cases of the Na-K-ATPase, carrier-mediated lactate transport, and the acetylcholine receptor (Yeagle, 1991; Grunze et al., 1980; Craido et al., 1982; Fong and McNamee, 1986). Several lines of evidence have linked alterations in cholesterol metabolism and transport to AD. The E4 allele of ApoE is associated with higher plasma cholesterol levels (Sing and Davignon, 1985), and ApoE4 is present with increased frequency in patients with sporadic and late onset familial AD (Strittmatter et al., 1993; Saunders et al., 1993; Corder et al., 1993). In addition, hypercholesterolemia is one of the major risk factors for critical coronary artery disease (cCAD), a condition that results in A deposition 3-10 times more frequently than in non-heart disease controls (Sparks et al., 1990, 1993). We report that methyl--cyclodextrin-solubilized cholesterol increases the levels of both mature and immature APP holoproteins in a dose-dependent fashion while dramatically reducing the production of APP.

MATERIALS AND METHODS

Transfections and Cell Lines

Antibodies and Radiolabeled Immunoprecipitation Assay

Conditioned media were used without modification and incubated with 22C11 or 4G8. Cells were rinsed once with PBS and removed from the plate with PBS, 0.02% EDTA. Cells were lysed in PBS plus 0.1% SDS, 1% Triton X-100, 0.5% deoxycholate, 1 mM phenylmethylsulfonyl fluoride, and 100 kallikrein-inactivating units/ml of aprotinin (PBS-TDS). Lysates were incubated with antiserum 8256. In all cases the primary antibody-antigen complex was precipitated with Protein A-Sepharose (Pharmacia Biotech Inc.) in PBS-TDS. Immunoprecipitated proteins were resolved on a 10%/16% Tris-Tricine gel (Schagger and Von Jagow, 1987). Gels were fluorographed (DuPont NEN), dried, and exposed to Kodak X-Omat film.

Immunoblotting

RESULTS AND DISCUSSION

Cholesterol, water solubilized by methyl--cyclodextrin at a ratio of 46 mg of cholesterol/g of solid, was delivered to human embryonic kidney (HEK) 293 cells stably transfected with APP 751. The cholesterol exchange between cyclodextrin and membranes reaches equilibrium in less than 1 min and is proportional to the concentration of cyclodextrin used (Irie et al., 1992a). Cyclodextrin-solubilized cholesterol, at the doses used here, has been shown to be an effective delivery system for cell culture studies as well as parenteral administration to animals (De Caprio et al., 1992; Irie et al., 1992a, 1992b).

We used this delivery system to determine if cholesterol modulation affected the stability of APP, a transmembrane protein with a half-life of only 20-30 min (Kang et al., 1987; Weidemann et al., 1989). Following a 24-h incubation to allow for intracellular distribution and membrane turnover, the APP 751 stably transfected HEK 293 cells were labeled for 8 h with S-labeled methionine/cysteine in the presence of cholesterol to obtain steady-state measurements. During the entire procedure, at all concentrations of cholesterol used, the cells remained attached to the plates; at 240 mg/dl they were slightly rounded, but at 160, 80, and 40 mg/dl cholesterol they looked indistinguishable from controls (data not shown). Cell lysates were used for immunoprecipitation of APP holoproteins with C-terminal polyclonal antiserum 8256 , previously characterized in Bodovitz et al.(1995). Antiserum 8256 immunoprecipitated two bands of 110 and 130 kDa, which correspond, respectively, to immature and mature APP holoprotein (Fig. 1a). Both protein bands increased significantly following the addition of cyclodextrin-solubilized cholesterol (Fig. 1a and Fig. 2, a and b). Mature APP holoprotein increased 50 ± 10% (p < 0.001; n = 6) at 40 mg of cholesterol/dl of media. (All values are normalized to no drug control and are given as ±S.E.; p values were determined by a Student's t test.) The peak increase of 160 ± 37% (p < 0.05; n = 4) occurred at 160 mg/dl cholesterol, followed by a smaller increase of 70 ± 14% (p < 0.05; n = 6) at 240 mg/dl cholesterol. Immature APP holoprotein showed a similar rate of increase, e.g. 46 ± 10% at 40 mg/dl cholesterol and 140 ± 64% at 160 mg/dl cholesterol (p < 0.001; n = 4), but was still increasing 660 ± 190% (p < 0.001; n = 6) at 240 mg/dl cholesterol.

Figure 1: Cholesterol modulation of mature and immature APP holoproteins and APP. HEK 293 cells stably transfected with APP 751 were preincubated with no drug or the indicated concentration (mg/dl) of methyl--cyclodextrin-solubilized cholesterol or methyl--cyclodextrin alone. The cells were changed to methionine/cysteine-free media containing the same concentration of cholesterol or cyclodextrin and labeled for 8 h with [S]methionine/cysteine. Cellular lysate was used to immunoprecipitate APP holoproteins with C-terminal antiserum 8256; conditioned media were used to immunoprecipitate the N-terminal -secretase derivative, APP, with monoclonal antibody 22C11. Immunoprecipitates were separated by 10% Tris/Tricine SDS-PAGE electrophoresis and visualized by autoradiography. Representative autoradiograms are shown. a, both mature and immature APP holoproteins are increased at 160 mg/dl cholesterol. Mature APP decreases at 240 mg/dl cholesterol, but immature APP continues to increase. c, APP decreases dramatically at 160 and 240 mg/dl cholesterol. The control band had to be overexposed in order for the autoradiogram to exhibit any APP at 240 mg/dl cholesterol. b, methyl--cyclodextrin was added at 0 or 5200 mg/dl; the latter corresponds to the amount used to solubilize 240 mg/dl cholesterol. This solubilization agent did not affect levels of immature or mature APP holoprotein. d, even at 5200 mg/dl, methyl--cyclodextrin did not affect levels of APP. These data demonstrate that the modulation of APP processing seen on the left was the result of cholesterol and not its solubilization agent.

Figure 2: Densitometric analysis of cholesterol modulation of APP holoproteins and APP. Autoradiograms were scanned into the computer, and bands corresponding to mature APP, immature APP, and APP were densitometrically analyzed with the Metamorph imaging system. a and b, increased cellular cholesterol loading increased the steady-state levels of mature and immature APP holoproteins. The increase in mature protein reached a peak and then began to decline, although still remaining above control levels at the highest cholesterol dose used, 240 mg/dl. By contrast, the levels of immature protein were still dramatically increasing at 240 mg/dl cholesterol. c, increased cellular cholesterol loading decreased APP levels. The change in level lagged behind the changes seen with the holoproteins at low doses but reached a 93 ± 1% (p < 0.001; n = 6) decrease at 240 mg/dl cholesterol. (All values are normalized to no drug control and are given as ±S.E.; p values were determined by a Student's t test; n = 4 for cholesterol doses of 80 and 160 mg/dl; n = 6 for cholesterol doses of 40 and 240 mg/dl.) *, p < 0.05;**, p < 0.01;***, p < 0.001.

The modulation of APP holoproteins suggested that downstream catabolites would also be modulated. To test this possibility we immunoprecipitated A and the N-terminal -secretase derivative, APP (see below for characterization), from the conditioned media of APP 751 stably transfected HEK 293 cells using, respectively, A monoclonal antibody 4G8 (as characterized by Buxbaum et al.(1992)) and N-terminal monoclonal antibody 22C11 (Boehringer Mannheim). Although A levels showed no consistent change (data not shown), APP significantly and reproducibly decreased in the presence of augmented cholesterol (Fig. 1c and 2c). The decrease was 16 ± 8% at 40 mg/dl cholesterol, indicating that APP levels were not as sensitive as holoprotein levels to low doses of cholesterol. The decrease was 65 ± 9% (p < 0.05; n = 4) at 160 mg/dl cholesterol and 93 ± 1% (p < 0.001; n = 6) at 240 mg/dl cholesterol, indicating a strong response to higher doses of cholesterol.

The N-terminal soluble APP derivative can be released into conditioned media by either - or -secretase cleavage. In order to determine the relative amounts of each cleavage in our system, we immunoprecipitated the total N-terminal derivative from conditioned media, split the precipitates in half, and resolved them on two separate SDS-PAGE gels. The proteins were transferred to membrane and probed with either 22C11, a monoclonal antibody against the N terminus of APP, or 6E10, a monoclonal antibody against residues 1-16 of A (Pirtilia et al., 1995). 22C11 recognizes total N-terminal derivative whereas 6E10 recognizes that resulting from - but not -secretase cleavage. Both antibodies recognized bands of similar intensity (Fig. 3). This finding, in conjunction with the sequence analysis of Wang et al.(1991), demonstrates that the soluble N-terminal APP derivative released into the conditioned media of HEK 293 cells is almost exclusively APP, the -secretase cleavage derivative.

Figure 3: Characterization of the N-terminal APP secretase derivative released into the conditioned media. N-terminal secretase derivative, in total, was immunoprecipitated from conditioned media with monoclonal antibody 22C11. The precipitate was split in half and resolved on two separate SDS-PAGE gels. The proteins were transferred to membrane and probed with either 22C11, a monoclonal antibody against the N terminus of APP, or 6E10, a monoclonal antibody against residues 1-16 of A. 22C11 recognizes the total N-terminal derivative whereas 6E10 recognizes that resulting from - but not -secretase cleavage. Both antibodies recognized bands of similar intensity. This finding, in conjunction with the sequence analysis of Wang et al.(1991), demonstrates that the soluble N-terminal APP derivative released into the conditioned media of HEK 293 cells is almost exclusively APP, the -secretase cleavage derivative.

In order to determine that the modulation of APP processing by cholesterol was not affected by methyl--cyclodextrin, the solubilization agent, we added this agent to our stably transfected cell system and immunoprecipitated APP holoproteins and APP. The concentration used, 5200 mg/dl, corresponded to the solubilization of 240 mg/dl cholesterol. Even at this high concentration, methyl--cyclodextrin did not affect levels of APP holoprotein (Fig. 1b) or levels of APP (Fig. 1d).

As a further control for the methyl--cyclodextrin-solubilized cholesterol delivery system, we immunoprecipitated APP holoproteins and APP from cells maintained in delipidated serum and treated with ethanol-solubilized cholesterol. This delivery system, in the same concentration range used here, has been shown to induce a significant linear increase in cellular free cholesterol (Lasa et al., 1991). Ethanol-solubilized cholesterol, in contrast to cyclodextrin-solubilized cholesterol (Fig. 1a), did not modulate APP holoprotein levels (Fig. 4a). The reason for the difference between the two delivery systems is unknown but could be a result of variation in the intracellular distribution of cholesterol; differential distribution might be the result of cyclodextrin, but not ethanol, mediating both cholesterol influx and efflux at the plasma membrane (Irie et al., 1992a). However, the impact of ethanol-delivered cholesterol on APP was dramatic, with reductions even more pronounced than seen with cyclodextrin-solubilized cholesterol (Fig. 4b). Levels of APP were greatly reduced with as little as 40 mg/dl cholesterol and all but gone at 80 mg/dl and higher (Fig. 4b). Both delivery systems thus support our major finding that increased cellular cholesterol dramatically inhibits -secretase cleavage.

Figure 4: Ethanol-solubilized cholesterol modulation of APP holoproteins and APP. As a control for the methyl--cyclodextrin-solubilized cholesterol delivery system, we immunoprecipitated APP holoproteins and APP from cells maintained in delipidated serum and treated with ethanol-solubilized cholesterol. a, this delivery system, in contrast to cyclodextrin-solubilized cholesterol, did not modulate APP holoprotein levels. The reason for the difference between the two delivery systems is unknown but could be a result of variation in the intracellular distribution of cholesterol; differential distribution might be the result of cyclodextrin, but not ethanol, mediating both cholesterol influx and efflux at the plasma membrane. b, the two delivery systems did, however, yield similar results on the modulation of APP, with ethanol-solubilized cholesterol generating an even more dramatic reduction. Levels of APP were greatly reduced at as little as 40 mg/dl cholesterol and all but gone at 80 mg/dl and higher. Both delivery systems, despite the differences in modulation of APP holoproteins, support our major finding that increased cellular cholesterol dramatically inhibits -secretase cleavage.

As a final control for our cyclodextrin delivery system, we examined the effects of methyl--cyclodextrin-solubilized cholesterol on general production of cellular and secreted proteins. We analyzed [S]methionine/cysteine-labeled proteins from cell lysate and conditioned media by 10% Tris/Tricine SDS-PAGE gel electrophoresis (Fig. 5). A small percentage of the cellular proteins changed in level, but there were no significant global differences in distribution or intensity between the spectra of labeled proteins, even at 240 mg/dl cholesterol (Fig. 5a). This lack of change indicates that cellular protein metabolism was largely unaffected by cholesterol modulation. By contrast, there were several changes in unimmunoprecipitated [S]methionine/cysteine-labeled secreted proteins (Fig. 5b). There was a decrease in a 120-kDa band with increasing cholesterol concentration; this band was APP. Its elevated levels in conditioned media were the result of the overexpression of the APP 751 gene in stably transfected HEK 293 cells. There were no other significant differences in the spectra of labeled secreted proteins between 0 and 160 mg/dl methyl--cyclodextrin-solubilized cholesterol. At 240 mg/dl cholesterol, however, one band at 65 kDa appeared, and several bands in the 40-kDa range increased in intensity. The increase is in opposition to the decrease in APP levels, demonstrating that the latter change is not due to nonspecific cholesterol modulation of secreted proteins.

Figure 5: Cholesterol modulation of general cellular and secreted proteins. Aliquots of the cellular lysates and conditioned media collected for use in the immunoprecipitation studies of Fig. 1were left unimmunoprecipitated, separated with 10% Tris/Tricine SDS-PAGE electrophoresis, and visualized by autoradiography. a, a small percentage of the [S]methionine/cysteine-labeled cellular proteins changed in level, but there were no significant global differences in distribution or intensity between the spectra of labeled proteins at cholesterol doses of 0, 160, or 240 mg/dl. This lack of change demonstrates that general protein metabolism was unaffected by cholesterol modulation. b, by contrast, there were several changes in unimmunoprecipitated [S]methionine/cysteine-labeled secreted proteins. There was a decrease in a 120-kDa band with increasing cholesterol concentration; this band was APP. Its elevated levels in conditioned media were the result of the overexpression of the APP 751 gene in stably transfected HEK 293 cells. There were no other significant differences in the spectra of labeled secreted proteins between 0 and 160 mg/dl cholesterol. At 240 mg/dl cholesterol, however, one band at 65 kDa appeared, and several bands in the 40-kDa range increased in intensity. The increase is in opposition to the decrease in APP levels, demonstrating the latter change is not due to nonspecific cholesterol modulation of secreted proteins.

The increase in APP stability with methyl--cyclodextrin-solubilized cholesterol is consistent with several experimental observations. APP is a transmembrane protein (Kang et al., 1987) that is tyrosine-sulfated and O- and N-glycosylated (Weidemann et al., 1989). APP only has a half-life of 20-30 min (Weidemann et al., 1989) but is found in many different intracellular membranes, including lysosomal and plasma (Haass et al., 1992), suggesting rapid intracellular movement. Increasing the cholesterol content of phospholipid bilayers increases their rigidity by ordering the acyl chain region and may slow down APP transport, in turn slowing down the transitions from immature to mature and mature to degraded. Even a small decrease in the rate of these transitions would have, given the short half-life of APP, a large effect on the net steady-state levels of mature and immature APP holoproteins.

Mature APP is cleaved by -secretase to generate APP, demonstrating a precursor-product relationship (Weidemann et al., 1989), yet augmenting methyl--cyclodextrin-solubilized cholesterol increases levels of mature APP while decreasing levels of APP. -Secretase function thus is reduced, either directly or indirectly. Indirectly, function would be reduced if enzyme and substrate were compartmentalized and if cholesterol were to block APP access to the protease-containing compartment. Cholesterol also could have a direct effect on -secretase activity, which appears to be membrane-associated. -Secretase cleavage requires that APP be inserted into a membrane, and it cleaves APP at a fixed distance from the membrane instead of at a specific amino acid sequence (Sisodia, 1992). Furthermore, cleavage is blocked by APP site-directed mutagenesis of three adjacent lysines to glutamic acid residues, located just carboxyl to the proposed transmembrane domain (Usami et al., 1993); this substitution demonstrated that perturbation of the association of APP with the membrane inhibits -secretase cleavage. Another perturbation may be the result of the stiffening of the membrane due to cholesterol loading, possibly inhibiting lateral movement and the required contact between enzyme and substrate (Fig. 6). Modulation of membrane fluidity also affects the external accessibility of membrane proteins, as evidenced by the complex changes in ligand binding of the serotonin receptor as a function of membrane fluidity (Heron et al., 1980). A change in the external accessibility of either -secretase or APP may inhibit the enzyme activity by disrupting a cleavage event that occurs at a fixed distance from the membrane.

Figure 6: Possible mechanism of the inhibition of -secretase cleavage by cholesterol. The stiffening of the membrane due to cholesterol loading may decrease -secretase cleavage of APP by inhibiting lateral movement (indicated by horizontal arrows) and the required contact between enzyme and substrate.

If cholesterol were to increase in the AD brain, our data from the cyclodextrin delivery system suggest an increase in immature and mature APP holoprotein and a decrease in APP. The significance of the former change is, at present, unclear. APP may function as a receptor (Kang et al., 1987; Ferreira et al., 1993; Nishimoto et al., 1993) and may be associated with the heterotrimeric G-protein, G (Nishimoto et al., 1993); its overproduction could lead to aberrant intracellular signaling. Alternatively, the main function of APP may be to serve as a precursor for APP and other cleavage derivatives. A decrease in APP would be the reduction of a mitogenic and trophic factor as well as a protective agent against hypoglycemic damage and glutamate toxicity (Araki et al., 1991; Schubet et al., 1989; Mattson et al., 1993). The loss of such a protein could exacerbate the cell death in AD.

Some evidence is available to suggest that cholesterol levels increase in AD. There is a predisposition for AD associated with the E4 allele of the cholesterol and lipid transport protein ApoE (Strittmatter et al., 1993; Saunders et al., 1993; Corder et al., 1993). Lipoproteins associated with ApoE4 are cleared more efficiently than those containing either of the other two alleles, E3 or E2 (Poirier et al., 1993), yet the E4 allele is linked to higher plasma cholesterol levels (Sing and Davignon, 1985) and is the most common of the three alleles in hypercholesterolemia (Utermann, 1984). The discrepancy stems from the efficient clearing of ApoE4 in the liver, possibly leading to a down-regulation of the low density lipoprotein receptor and, hence, an elevation of serum low density lipoprotein cholesterol (for review, see Davignon et al.(1988)).

Hypercholesterolemia is one of the major risk factors for cCAD, a condition that often results in A deposition similar to that found in AD (Sparks et al., 1990, 1993). Cerebral A plaques are 3-10 times more common in cCAD than in nonheart disease controls (Sparks et al., 1993). In addition, hypercholesterolemia induced in rabbits resulted in elevated immunoreactivity of A and ALZ-50, an epitope only found in mature brain afflicted by AD (Sparks et al., 1994). All of these data suggest that increased cholesterol levels are a risk factor for AD. Our data provide a mechanism, namely the direct disruption of APP processing.

FOOTNOTES

*

This work was supported by the National Institutes of Health Grant AG10481, the Alzheimer's Association, and the Boothroyd Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence and reprint requests should be addressed: Dept. of Neurobiology and Physiology, Northwestern University, 5-110 Hogan Hall, 2153 Sheridan Rd., Evanston, IL 60208.

()

The abbreviations used are: APP, amyloid precursor protein; APP, soluble N-terminal secretase derivative of amyloid precursor protein; AD, Alzheimer's disease; cCAD, critical coronary artery disease; HEK, human embryonic kidney; PBS, phosphate-buffered saline; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine; PAGE, polyacrylamide gel electrophoresis.

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