Impaired cholesterol esterification in the plasma in patients with breast cancer

An important factor which determines the movement of cholesterol in and out of the cells is the free cholesterol (FC)/esterified cholesterol (EC) ratio in the plasma. Although this ratio has been shown to be increased in several types of malignancies in humans as well as experimental animals, it is not known whether such an abnormality is found in breast cancer patients. Furthermore, the reasons for such an increase in cancer patients are unknown. We studied the plasma lipid composition and the activity of lecithin-cholesterol acyltransferase (LCAT), the enzyme responsible for the formation of most of EC in human plasma, in 12 women with breast cancer and 9 agematched control women. The plasma EC concentration was found to be significantly decreased in cancer patients, whereas the FC concentration was unchanged, leading to increased FC/EC ratios (P<0.05). The concentration of phosphatidylcholine, the acyl donor in the LCAT reaction, was decreased significantly, whereas all other phospholipids were unaffected. The cholesterol-esterifying activity of LCAT was significantly lower in cancer patients, whether assayed with endogenous substrates (P<0.05), or with an exogenous substrate (P<0.01). However, another function of the enzyme, namely the lysolecithin acyltransferase activity, was increased (P<0.02), indicating that the enzyme concentration in plasma may not be decreased. These results show that the increase in the FC/EC ratio in cancer patients is due to an impaired esterification of cholesterol by plasma LCAT, probably due to an alteration in the composition of substrate lipoproteins, or the presence of an inhibitory factor.     

Effectiveness of resistant starch,compared to guar gum,in depressing plasma cholesterol and enhancing fecal steroid excretion

Amylase-resistant starch (RS) represents a substrate that can be administered in substantial amounts in the diet, in contrast to gel-forming polysaccharides, such as guar gum (GG). The aim of this work was thus to compare the effects of GG and RS on cholesterol metabolism in rats adapted to 0.4% cholesterol diets, using dietary GG or RS levels (8 or 20%, respectively) that led to a similar development of fermentations, as assessed by the degree of enlargement of the cecum. The RS diet elicited a marked rise in the cecal pool of short-chain fatty acids, especially acetic and butyric acid, whereas the GG diet favored high-propionic acid fermentations. Both polysaccharides markedly altered the cholesterol excretion, from 50% of ingested cholesterol in controls, up to about 70% in rats adapted to the RS or GG diets. With these diets, the fecal excretion of bile acids was enhanced (67 and 144% with the RS and GG diets, respectively). RS and GG diets were effective in lowering plasma cholesterol (about −40%) and triglycerides (−36%). There was practically no effect of the diets on cholesterol in d>1.040 lipoproteins (high density lipoproteins), whereas RS (and to a larger extent, GG) were very effective to depress cholesterol in d<1.040 lipoproteins (especially in triglyceride-rich lipoproteins). Fermentable polysaccharides counteracted the accumulation of cholesterol in the liver, especially cholesterol esters. In parallel, liver acyl CoA:cholesterol acyltransferase was depressed in rats fed the RS or GG diets, whereas only the GG diet counteracted the downregulation of 3-hydroxy-3-methylglutaryl-CoA by cholesterol. These data suggest that RS may be practically as effective as a gel-forming gum, such as GG, on steroid excretion and on cholesterol metabolism.     

Effects of cholesterol oxidation derivatives on cholesterol esterifying and cholesteryl ester hydrolytic enzyme activity of cultured rabbit aortic smooth muscle cells

The effects of 5 μg/ml of 25-hydroxycholesterol; cholestane-3β, 5α,6β-triol; and cholesterol on acyl CoA cholesterol acyltransferase, acid cholesteryl ester hydrolase and neutral cholesteryl ester hydrolase was studied in cultured rabbit aortic smooth muscle cells. After 1 hour incubation, 25-hydroxycholesterol resulted in a fourfold stimulation of acyl CoA cholesterol acyltrans-ferase activity. No stimulation by 25-hydroxycholesterol was noted before 15 minutes or after 5 hours of incubation. Neither cholestane-3β,5α,6β-triol nor cholesterol influenced acyl CoA cholesterol acyltransferase activity at any time interval. No significant effects of any of the sterols were noted on acid cholesteryl ester hydrolase or neutral cholesteryl ester hydrolase activity. The imbalance between acyl CoA cholesterol acyl trans-ferase and hydrolase activities induced by 25-hydroxycholesterol could result in cholesteryl ester accumulation by arterial smooth muscle cells, which may be associated with atherosclerosis.     

Effect of synthetic antioxidants on cholesterol stability during the thermal-induced oxidation of a polyunsaturated vegetable oil

As a molecule with an unsaturated bond, cholesterol is prone to oxidation. Cholesterol oxidation products (COP) are found in many common foods and have been shown to be atherogenic, cytotoxic, mutagenic, and possibly carcinogenic. Efforts to reduce the formation of oxidation products are considered important during the manufacture and processing of foods. The effect of synthetic antioxidants on cholesterol oxidation has not been extensively studied. We assayed the effect of five commonly used antioxidants—BHT, BHA, the n-propyl ester of 3,4,5-trihydroxy benzoic acid (PG), TBHQ, and 6-ethoxy-1,2-dihydro-2,4-trimethylquinoline (EQ)—on cholesterol stability when oxidation is induced in a Rancimat 679 instrument by bubbling air through the sample at 150°C. The sample consisted of 200 mg cholesterol dispersed in 100 g of a polyunsaturated vegetable oil (soybean oil). Formation of six COP was measured at the induction period, and at the 50 and 100 μS conductivity values. Under the experimental conditions, BHT and TBHQ were the most effective inhibitors of cholesterol oxidation. BHA and EQ were less effective, and PG was unable to prevent cholesterol oxidation. Synthetic antioxidants were more effective in preventing COP formation at the nucleus of the cholesterol structure than at the lateral chain.     

Serum Opacity Factor Enhances HDL-Mediated Cholesterol Efflux,Esterification and Anti Inflammatory Effects

Serum opacity factor (SOF) is a streptococcal protein that disrupts the structure of human high density lipoproteins (HDL) releasing lipid-free apo A-I while forming a large cholesteryl ester-rich particle and a small neo HDL. Given its low cholesterol and high phospholipid contents, we tested the hypotheses that neo HDL is a better substrate for cholesterol esterification via lecithin:cholesterol acyltransferase (LCAT), better than HDL as an acceptor of THP-1 macrophage cholesterol efflux, and improves reduction of oxidized LDL-induced production of inflammatory markers. We observed that both cholesterol efflux and esterification were improved by recombinant (r)SOF treatment of whole plasma and that the underlying cause of the improved cholesterol esterification in plasma and macrophage cholesterol efflux to rSOF-treated plasma was due to the rSOF-mediated conversion of HDL to neo HDL. Moreover, the reduction of secretion of TNF-α and IL-6 by THP-1 cells by neo HDL was twice that of HDL. Studies in BHK cells overexpressing cholesterol transporters showed that efflux to neo HDL occurred primarily via ABCA1 not ABCG1. Thus, rSOF improves two steps in reverse cholesterol transport with a concomitant reduction in the release of macrophage markers of inflammation. We conclude that rSOF catalyzes a novel reaction that might be developed as a new therapy that prevents or reverses atherosclerosis via improved reverse cholesterol transport.     

Net lipid transfer between lipoproteins in fish-eye disease plasma supplemented with normal high density lipoproteins

Native fish-eye disease plasma, which is deficient of both high density lipoproteins (HDL) and lecithin-cholesterol acyltransferase activity (α-LCAT), processing the free cholesterol of these lipoproteins, has been supplemented with normal isolated HDL₂ or HDL₃ and incubated in vitro at 37 C. After incubation for 0,7.5 and 24 hr the very low density (VLDL) and low density (LDL) lipoproteins as well as HDL were isolated, and their contents of triglycerides, phospholipids and free, esterified and total cholesterol were quantified. The resulting net mass transfer of the different lipids revealed a functioning transfer of cholesteryl esters and all other analyzed lipids between the lipoproteins, although no de novo esterification of the HDL cholesterol by LCAT in this plasma occurred. In accordance with previous findings there was a functioning esterification process of the free cholesterol of the combined VLDL and LDL of fish-eye disease plasma. The present results make it reasonable to conclude that the lack of HDL cholesterol esterification in this disease is not a result of a deficiency of cholesteryl ester transfer or lipid transfer activities.     

Utilization of various sterols by lecithin-cholesterol acyltransferase as acyl acceptors

Highly purified lecithin-cholesterol acyltransferase of human plasma was used to study the utilization of various sterols as the acyl acceptor. The esterification of sterols was facilitated by the presence of a 3β-hydroxyl group and thetrans configuration of the A/B rings, as was evident from the lack of acceptor activity of all 3α-hydroxy sterols tested and coprostanol. Cholesterol analogs in which the side chain is modified, such as campesterol, β-sitosterol, desmosterol and stigmasterol, were less effective than cholesterol as acyl acceptors. However, androstan-3β-o1, which completely lacks the side chain, was found to be more active than cholesterol. The transfer of the acyl group to all effective sterols required the presence of the cofactor peptide apolipoprotein A-I.     

Possible Role of Different Yeast and Plant Lysophospholipid:Acyl-CoA Acyltransferases (LPLATs) in Acyl Remodelling of Phospholipids

Recent results have suggested that plant lysophosphatidylcholine:acyl‐coenzyme A acyltransferases (LPCATs) can operate in reverse in vivo and thereby catalyse an acyl exchange between the acyl‐coenzyme A (CoA) pool and the phosphatidylcholine. We have investigated the abilities of Arabidopsis AtLPCAT2, Arabidopsis lysophosphatidylethanolamine acyltransferase (LPEAT2), S. cerevisiae lysophospholipid acyltransferase (Ale1) and S. cerevisiae lysophosphatidic acid acyltransferase (SLC1) to acylate lysoPtdCho, lysoPtdEtn and lysoPtdOH and act reversibly on the products of the acylation; the PtdCho, PtdEtn and PtdOH. The tested LPLATs were expressed in an S. cervisiaeale1 strain and enzyme activities were assessed in assays using microsomal preparations of the different transformants. The results show that, despite high activity towards lysoPtdCho, lysoPtdEtn and lysoPtdOH by the ALE1, its capacities to operate reversibly on the products of the acylation were very low. Slc1 readily acylated lysoPtdOH, lysoPtdCho and lysoPtdEtn but showed no reversibility towards PtdCho, very little reversibility towards PtdEtn and very high reversibility towards PtdOH. LPEAT2 showed the highest levels of reversibility towards PtdCho and PtdEtn of all LPLATs tested but low ability to operate reversibly on PtdOH. AtLPCAT2 showed good reversible activity towards PtdCho and PtdEtn and very low reversibility towards PtdOH. Thus, it appears that some of the LPLATs have developed properties that, to a much higher degree than other LPLATs, promote the reverse reaction during the same assay conditions and with the same phospholipid. The results also show that the capacity of reversibility can be specific for a particular phospholipid, albeit the lysophospholipid derivatives of other phospholipids serve as good acyl acceptors for the forward reaction of the enzyme.     

Oxidative effects of animal-originated porphyrins and riboflavin on cholesterol oxidation in an aqueous model system

This study was executed to investigate effects of animal-originated porphyrins and riboflavin on cholesterol oxidation in aqueous model systems. Changes of headspace oxygen contents, cholesterol, and cholesterol oxide products (COP) in the model systems were measured by gas chromatography during storage under light. As concentration of protoporphyrin increased, contents of headspace oxygen decreased and COP increased. The same trend as that of protoporphyrin occurred with riboflavin in terms of contents of headspace oxygen, but production of COP was the highest at 5 ppm riboflavin. As concentrations of hemoglobin and myoglobin increased, headspace oxygen content and COP production were not changed significantly. Consequently, protoporphyrin could be the most active catalyst on the cholesterol oxidation in the aqueous system, but myoglobin and hemoglobin did not accelerate cholesterol oxidation.     

The hypotriglyceridemic effect of eicosapentaenoic acid in rats is reflected in increased mitochondrial fatty acid oxidation followed by diminished lipogenesis

The effect of eicosapentaenoic acid (EPA) on fatty acid oxidation and on key enzymes of triglyceride metabolism and lipogenesis was investigated in the liver of rats. Repeated administration of EPA to normolipidemic rats resulted in a time-dependent decrease in plasma triglycerides, phospholipids and cholesterol. The triglyceride-lowering effect was observed after one day of feeding whereas lowering of plasma cholesterol and phospholipids was observed after five days of treatment. The triglyceride content of liver was reduced after two-day treatment. At that time, increased mitochondrial fatty acid oxidation occurred whereas mitochondrial and microsomal glycerophosphate acyltransferase was inhibited. The phosphatidate phosphohydrolase activity was unchanged. Adenosine triphosphate:citrate lyase, acetyl-CoA carboxylase, fatty acid synthetase and glucose-6-phosphate dehydrogenase were inhibited during the 15 d of EPA treatment whereas peroxisomal β-oxidation was increased. At one day of feeding, however, when the hypotriglyceridemic effect was established, the lipogenic enzyme activities were reduced to the same extent in palmitic acid-treated animals as in EPA-treated rats. In cultured rat hepatocytes, the oxidation of [¹⁴C]palmitic acid to carbon dioxide and acid-soluble products was stimulated in the presence of EPA. These results suggest that the instant hypolipidemia in rats given EPA could be explained at least in part by a sudden increase in mitochondrial fatty acid oxidation, thereby reducing the availability of fatty acids for lipid synthesis in the liver for export,e.g., in the form of very low density lipoproteins, even before EPA induced peroxisomal fatty acid oxidation, reduced triglyceride biosynthesis and diminished lipogenesis.     

Cholesterol Oxidation is Increased and PUFA Decreased by Frozen Storage and Grilling of Atlantic Hake Fillets (<Emphasis Type="Italic">Merluccius hubbsi</Emphasis>)

Fresh fillets of Atlantic hake were stored at −18 °C for 120 days and changes in lipid composition and the formation of cholesterol oxidation products (COP) during storage and subsequent grilling were evaluated. Fresh hake showed low COP levels (8.0 μg/g, dry basis); however, a significant increase in COP (P < 0.02) and a concomitant decrease in the cholesterol and polyunsaturated fatty acids content during frozen storage and after grilling were observed. The main cholesterol oxides present in the analyzed samples were: 19-Hydroxycholesterol, 24(S)-hydroxycholesterol, 22(S)-hydroxycholesterol, 25-hydroxycholesterol, 25(R)-hydroxycholesterol and 7-Ketocholesterol. The oxides which were more influenced by the thermal treatment were 24(S)-OH and 25(R)-OH; however, after 120 days of storage 7-ketocholesterol was the main product formed. Frozen storage and subsequent grilling under domestic conditions are important factors in damage of cholesterol and unsaturated fatty acids levels, with consequent production of cholesterol oxides, although the mechanism of the formation of these compounds by the different processes is probably different. An erratum to this article can be found at     

Properties of the glycerol acylating enzymes in microsomal preparations from the developing seeds of safflower (Carthamus tinctorius) and turnip rape (Brassica campestris) and their ability to assemble cocoa-butter type fats

Microsomal membrane preparations from the developing seeds of safflower (Carthamus tinctorius, var. Gila) and turnip-rape (Brassica campestris, var. Bele) catalyzed the assembly of triacylglycerols (triglycerides) from sn-glycerol 3-phosphate and acyl-CoA. The membrane preparations were used to assess the acyl specificity properties of the initial acylating enzymes—glycerol 3-phosphate acyltransferase (GPAT) and 1-acylglycerol 3-phosphate acyltransferase (lysophosphatidic acid acyltransferase, LPAAT)—that are responsible for the fatty acids at positions sn-1 and sn-2 of the sn-triacylglycerol, respectively. In spectrophotometric assays it was possible to evaluate, to some extent, how these enzymes will utilize unusual and foreign fatty acids that are not normally found in these particular plant species. The acylating enzymes from both plants used, to varying extents, a comprehensive range of acyl-CoA donor species and some kinetic properties of the substrates involved are presented. The enzymes from safflower, however, were generally the more selective, whereas the turnip-rape was less particular and could utilize a range of acyl substrates. The enzymes from both plants hardly utilized erucate (C22∶1), and the significance of this is discussed in terms of mechanisms which have evolved in order to exclude certain, perhaps detrimental, fatty acids from structural membrane lipids and dedicate them to storage lipid assembly. The ability of the microsomal preparations, from the developing seeds of both plants, to synthesize cocoabutter type fats was investigated. Microsomal membranes were incubated with glycerol 3-phosphate and equimolar amounts of palmitate, oleate and stearate. Safflower preparations catalyzed the construction of sn-triacylglycerol with largely palmitate, oleate and stearate in positions sn-1, 2 and 3, respectively. The selectivity for acyl species in rape was less pronounced, however, substantial saturated-unsaturated-saturated oils were still produced. The results are discussed in terms of the acyl selectivity properties of the glycerol acylating enzymes. It is evident that given the correct composition of fatty acids, the plant can produce cocoabutter or other exotic fats.     

Enzymatic formation of cholesteryl ester from cholesterol by gallbladder mucosa

The formation of cholesteryl ester from cholesterol and acyl CoA catalyzed by the enzyme acyl CoA: cholesterol acyltransferase (EC 2.3.1.26) was studied in guinea pig gallbladder mucosa homogenate and the subcellular fractions. The enzymatic activity was enriched in the microsomal fraction. Highest activity was observed with palmitoyl, stearoyl or oleoyl CoA as substrate. Lowest activity was observed with linoleoyl CoA. These data elucidate one mechanism for the formation of cholesteryl ester from cholesterol by the gallbladder wall.     

Effects of diet and high density lipoprotein subfractions on the removal of cellular cholesterol

The effects of isocaloric substitutions of dietary polyunsaturated and saturated fat on the composition and function of plasma high density lipoproteins (HDLs) were studied in 3 normal subjects who were fed saturate-rich and polyunsaturate-rich diet programs. Compared to the saturated diets (P/S=0.4), polyunsaturated fat diets (P/S=4 or 2) reduced both plasma cholesterol and triglyceride levels. In 2 of the subjects, HDL cholesterol concentrations increased with polyunsaturated fat caused a reduction in HDL fatty acyl content of oleate and an increase in linoleate. To determine whether the altered composition affected the removal of cell membrane cholesterol, HDL and their subfractions, HDL₂ and HDL₃, which were isolated from each of the diets, were incubated with Ehrlich ascites cells in vitro. The cells were prelabeled with [³H] cholesterol, and the release of labeled cholesterol from the cells into the medium containing the various HDL fractions was determined. HDL, irrespective of the type of dietary fat, caused a release of [³H] cholesterol from the cells into the medium. The amount of [³H] cholesterol recovered in the medium was dependent on the absolute concentration of HDL cholesterol added to the cells and was independent of the type of diet. These results indicate that HDL facilitates the removal of cholesterol from cells, but that the amount and rate of removal are independent of the changes in HDL composition that can be obtained by dietary perturbations.     

Cholesterol metabolism in frog (Rana esculenta) liver: Seasonal and sex-related variations

Many aspects of lipid metabolism have been studied in amphibians, but seasonal lipid modulation in male and female frogs has not been investigated. We describe here the yearlong patterns of hepatic lipid content and enzyme activities related to cholesterol homeostasis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and acyl coenzyme A:cholesterol acyltransferase (ACAT) activity in liver of the male and female frog,Rana esculenta. Lipid storage follows distinct seasonal patterns, with an increase in June that is more pronounced in the female than in the male frog. Cholesterol content and cholesterol storage as cholesteryl ester in male liver are consistent with the activity of HMG-CoA reductase and of ACAT enzymes. HMG-CoA reductase activity of the female frog shows an extra peak in fall unrelated to cholesterol storage and probably related to the production of essential compound for oogenesis.     

Inhibition of acyl CoA: Cholesterol acyltransferase and sterologenesis in rat liver by diazepam,In vitro

Diazepam, a commonly prescribed tranquilizer, was found to inhibit cholesterol biosynthesis in rat liver minces; inhibition appeared to occur at multiple post-mevalonate sites. Diazepam also inhibited cholesterol esterification by acylCoA:cholesterol acyltransferase in isolated liver microsomes and minces. Liver minces incubated with [¹⁴C] oleate demonstrated increased uptake of the fatty acid and a greater incorporation of the substrate into triglycerides, diglycerides and phospholipids when diazepam was present. The results suggest possible mechanisms for the hypocholesterolemic effect of diazepam in experimental animals and for the elevation of triglycerides and very low-density lipoproteins in man and the rat.     

Effects of frying and storage on cholesterol oxidation in minced meat products

The presence of cholesterol oxidation products (COP) in the diet is a health concern for their various known adverse effects. It is important that the generation of COP be assessed during different stages of production, handling, and storage of meats and meat products so that relevant measures can be taken to minimize the production of COP. In a preliminary study, we investigated the content of COP in the lipids of raw meatballs (50% prok+50% beef), prefried meatballs (50% pork +50% beef), raw hamburger (100% beef), and prefried burger (50% pork+50% beef). Six of the common COP, viz 7α- and 7β-hydroxycholesterol, 7-ketocholesterol, 5α,6α-epoxycholestanol, 5β,6β-epoxycholestanol, and cholestanetriol, were analyzed by gas chromatography (GC) and GC-mass spectroscopy. The total content of these COP was in the range of 7 to 10 μg/g lipids in raw meatballs, prefried meat balls, and raw hamburger, after frying these samples for consumption. The prefried hamburger had ca. 8μg/g lipids of the total COP before frying, and this amount increased to 29 μg/g lipids after frying. During the storage of this fried sample, the total COP increased to 42 and 50 μg/g lipids, after 1 and 2 wk of storage, respectively. The results of this study show that freshly prepared meat products are a minor source of COP in the diet. However, if semiprepared frozen meat products are fried once and then stored for future consumption, the levels of COP can increase considerably, and this may be of concern for certain groups of consumers. Presented in part as a poster at the 88th AOCS Annual Meeting and Exposeattle, WA, May 11–14, 1997.     

Effects of perturbations in hepatic free and esterified cholesterol pools on bile acid synthesis,cholesterol 7α-hydroxylase,HMG-CoA reductase,acyl-CoA:Cholesterol acyltransferase and cytosolic cholesteryl ester hydrolase

Effects of expansion of the hepatic free cholesterol pool on bile acid and cholesterol metabolism and homeostasis were examined in rats fed cholesterol in high-fat diets or treated with oleyl-p-(n-decyl)-benzenesulfonate (ODS) or progesterone. Cholesterol feeding for 10–16 days, which increased free (33%) and esterified (6-fold) cholesterol, had no effect on cholate synthesis, total bile acid synthesis, or cholate turnover, whereas these activities were increased 60–80% by ODS and progesterone, which produced only small increases (19%) in free cholesterol. Cholesterol feeding reduced β-hydroxy-β-methylglutaryl (HMG)-CoA reductase (72%) and cholesteryl ester hydrolase (48%) and increased acyl-CoA:cholesterol acyltransferase (184%), whereas ODS and progesterone reversed these compensatory responses in cholesterol-fed rats. Cholesterol 7α-hydroxylase was changed no more than 22% by any treatment. A bolus of ODS elevated biliary cholesterol output 41% and shifted biliary bile acid synthesis and composition toward 12-deoxy bile acids. These effects were not seen in ODS-fed or progesterone-treated rats, in which cholesteryl ester stores were depleted. It is concluded that effects of free cholesterol on bile acid synthesis and biliary cholesterol are probably mediated by specific precursor or regulatory pools which can be independently regulated and which represent a relatively small fraction of hepatic free cholesterol.     

Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer’s disease and are neurotoxic when oxidized ex vivo

Brain regional oxidative damage is thought to be a central mechanism in the pathogenesis of Alzheimer’s disease (AD). Recent studies of cerebrospinal fluid (CSF) have suggested that increased lipid peroxidation of CSF and CSF lipoproteins also may occur in AD patients. In the present study, we determined the susceptibility of human CSF to ex vivo lipid peroxidation and tested the hypothesis that oxidized CSF lipoproteins may be neurotoxic. Whole CSF or a CSF lipoprotein fraction (d<1.210 g/mL) was oxidized with 2,2′-azobis(2-amidino-propane)dihydrochloride (AAPH), a hydrophilic free-radical generator. Kinetics of CSF lipid peroxidation were followed by a standard fluorescence product accumulation assay. Oxidation of AD CSF yielded significantly shorter fluorescent lag times than controls, indicating reduced antioxidant capacity. Electrophoretic mobilities of CSF apolipoproteins were specifically reduced upon oxidation of CSF with AAPH, suggesting that lipoproteins are primary targets of CSF lipid peroxidation. Cultured neuronal cells were exposed to physiological concentrations of isolated CSF lipoproteins oxidized with increasing concentrations of AAPH; the resulting neurotoxicity showed a significant linear AAPH concentration-response relationship. These results suggest that oxidized CSF lipoproteins may contribute to the pathogenesis of neurodegeneration in AD.