Highest terrestrial 3He/4He credibly from the core.

The observation that many lavas associated with mantle plumes have higher 3He/4He ratios than the upper convecting mantle underpins geophysical, geodynamic and geochemical models of Earth's deep interior. High 3He/4He ratios are thought to derive from the solar nebula or from solar-wind-irradiated material that became incorporated into Earth during early planetary accretion. Traditionally, this high-3He/4He component has been considered intrinsic to the mantle, having avoided outgassing caused by giant impacts and billions of years of mantle convection1-4. Here we report the highest magmatic 3He/4He ratio(67.2 ± 1.8 times the atmospheric ratio) yet measured in terrestrial igneous rocks, in olivines from Baffin Island lavas. We argue that the extremely high-3He/4He helium in these lavas might derive from Earth's core5-9. The viability of the core hypothesis relaxes the long-standing constraint-based on noble gases in lavas associated with mantle plumes globally-that volatile elements from the solar nebula have survived in the mantle since the early stages of accretion.

Helium and lead isotopes reveal the geochemical geometry of the Samoan plume.

Hotspot lavas erupted at ocean islands exhibit tremendous isotopic variability, indicating that there are numerous mantle components hosted in upwelling mantle plumes that generate volcanism at hotspots like Hawaii and Samoa. However, it is not known how the surface expression of the various geochemical components observed in hotspot volcanoes relates to their spatial distribution within the plume. Here we present a relationship between He and Pb isotopes in Samoan lavas that places severe constraints on the distribution of geochemical species within the plume. The Pb-isotopic compositions of the Samoan lavas reveal several distinct geochemical groups, each corresponding to a different geographic lineament of volcanoes. Each group has a signature associated with one of four mantle endmembers with low (3)He/(4)He: EMII (enriched mantle 2), EMI (enriched mantle 1), HIMU (high µ = (238)U/(204)Pb) and DM (depleted mantle). Critically, these four geochemical groups trend towards a common region of Pb-isotopic space with high (3)He/(4)He. This observation is consistent with several low-(3)He/(4)He components in the plume mixing with a common high-(3)He/(4)He component, but not mixing much with each other. The mixing relationships inferred from the new He and Pb isotopic data provide the clearest picture yet of the geochemical geometry of a mantle plume, and are best explained by a high-(3)He/(4)He plume matrix that hosts, and mixes with, several distinct low-(3)He/(4)He components.

A cyclic peptide that binds p75(NTR) protects neurones from beta amyloid (1-40)-induced cell death.

The current study determined the ability of a p75(NTR) antagonistic cyclic peptide to rescue cells from beta amyloid (Abeta) (1-40)-induced death. p75(NTR)-, p140(trkA)-NIH-3T3 cells or E17 foetal rat cortical neurones were incubated with 125I-NGF or 125I-Abeta (1-40) and increasing concentrations of the cyclic peptide (CATDIKGAEC). Peptide ability to displace 125I-NGF or 125I-Abeta (1-40) binding was determined. Duplicate cultures were preincubated with CATDIKGAEC (250 nM) or diluent and then stimulated with Abeta (1-40). Peptide ability to displace Abeta (1-40) binding, interfere with Abeta (1-40)-induced signalling and rescue cells from Abeta-mediated toxicity was determined by immunoprecipitation and autoradiography, Northern blotting, JNK activation, MTT and trypan blue assays. The peptide inhibited NGF and Abeta (1-40) binding to p75(NTR), but not to p140(trkA). Abeta (1-40) induced c-jun transcription (57.3% +/- 0.07%) in diluent-treated p75(NTR)-cells, but not in cells preincubated with the cyclic peptide. Also, at 250 nM, the peptide reduced Abeta (1-40)-induced phosphorylation of JNK by 71.8% +/- 0.03% and protected neurones against Abeta-induced toxicity as determined by: trypan blue exclusion assay (53% +/- 11% trypan blue-positive cells in diluent pretreated cultures vs. 28% +/- 5% in cyclic peptide-pretreated cultures); MTT assay (0.09 +/-0.03 units in diluent-pretreated cells vs. 0.12 +/- 0.004 units in cyclic peptide-pretreated cells); and visualization of representative microscopic fields. Our data suggest that a cyclic peptide homologous to amino acids 28-36 of NGF known to mediate binding to p75(NTR) can interfere with Abeta (1-40) signalling and rescue neurones from Abeta (1-40)-induced toxicity.

Modulation of endothelial cell migration by extracellular nucleotides: involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways.

Extracellular nucleotides bind to type-2 purinergic/pyrimidinergic (P2) receptors that mediate various responses, such as cell activation, proliferation and apoptosis, implicated in inflammatory processes. The role of P2 receptors and their associated signal transduction pathways in endothelial cell responses has not been fully investigated. Here, it is shown that stimulation of human umbilical vein endothelial cells (HUVEC) with extracellular ATP or UTP increased intracellular free calcium ion concentrations ([Ca(2+)](i)), induced phosphorylation of focal adhesion kinase (FAK), p130(cas) and paxillin, and caused cytoskeletal rearrangements with consequent cell migration. Furthermore, UTP increased migration of HUVEC in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner. BAPTA or thapsigargin inhibited the extracellular nucleotide-induced increase in [Ca(2+)](i), a response crucial for both FAK phosphorylation and cell migration. Furthermore, long-term exposure of HUVEC to ATP and UTP, agonists of the G protein-coupled P2Y2 and P2Y4 receptor subtypes, caused upregulation of alpha(v) integrin expression, a cell adhesion molecule known to directly interact with P2Y2 receptors. Our results suggest that extracellular nucleotides modulate signaling pathways in HUVEC influencing cell functions, such as cytoskeletal changes, cellular adhesion and motility, typically associated with integrin-activation and the action of growth factors. We propose that P2Y2 and possibly P2Y4 receptors mediate those responses that are important in vascular inflammation, atherosclerosis and angiogenesis.

Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3.

Patients with Gaucher disease have been classified as type 1 nonneuronopathic, type 2 acute neuronopathic, and type 3 chronic neuronopathic phenotypes. Increased quantities of glucocerebroside and glucosylsphingosine (glucopsychosine) are present in the brain of type 2 and type 3 Gaucher patients. Galactosylsphingosine has previously been shown to be neurotoxic in globoid cell leukodystrophy (Krabbe disease). To determine whether glucosylsphingosine is also neurotoxic, we examined its effect on cultured cholinergic neuron-like LA-N-2 cells. When these cells were exposed to 1, 5, or 10 microM glucosylsphingosine for a period of 18 h, they became shriveled, neurite outgrowth was suppressed, and the activities of the lysosomal enzymes glucocerebrosidase, sphingomyelinase, and beta-galactosidase were reduced in a dose-dependent manner. Acetylcholine in cells exposed to glucosylsphingosine also declined. Cells switched to glucosylsphingosine-free medium partially recovered. The data suggest that accumulation of glucosylsphingosine contributes to neuronal dysfunction and destruction in patients with neuronopathic Gaucher disease.

Synthesis of acetylcholine by lung cancer.

The role of autocrine growth factors in the stimulation of lung cancer growth is well established. Nicotine is an agonist for acetylcholine receptors and stimulates lung cancer growth. This suggests that if lung cancers synthesize acetylcholine (ACh), then ACh may be an autocrine growth factor for lung cancer. Analysis of normal lung demonstrated that the cells of origin of lung cancers express the proteins necessary for non-neuronal ACh storage and synthesis. Analysis of mRNA from squamous cell lung carcinoma, small cell lung carcinoma (SCLC) and adenocarcinoma showed synthesis of choline acetyltransferase (ChAT) and nicotinic receptors. Immunohistochemical analysis of a retrospective series of SCLC and adenocarcinomas showed that more than 50% of the lung cancers screened expressed ChAT and nicotinic receptors. To study the effect of endogenous ACh synthesis on growth, SCLC cell lines were studied. SCLC cell lines were found to express ChAT mRNA and to secrete ACh into the medium as measured by HPLC separation and enzymatically-coupled electrochemical detection. The SCLC cell line NCI-H82 synthesized highest levels of ACh. Showing that the endogenously synthesized ACh interacted with its receptors to stimulate cell growth, addition of muscarinic and nicotinic antagonists slowed H82 cell proliferation. These findings demonstrate that lung cancer cell lines synthesize and secrete ACh to act as an autocrine growth factor. The existence of a cholinergic autocrine loop in lung cancer provides a basis for understanding the effects of nicotine in cigarette smoke on lung cancer growth and provides a new pathway to investigate for potential therapeutic approaches to lung cancer.

Generation of choline for acetylcholine synthesis by phospholipase D isoforms.

BACKGROUND: In cholinergic neurons, the hydrolysis of phosphatidylcholine (PC) by a phospholipase D (PLD)-type enzyme generates some of the precursor choline used for the synthesis of the neurotransmitter acetylcholine (ACh). We sought to determine the molecular identity of the relevant PLD using murine basal forebrain cholinergic SN56 cells in which the expression and activity of the two PLD isoforms, PLD1 and PLD2, were experimentally modified. ACh levels were examined in cells incubated in a choline-free medium, to ensure that their ACh was synthesized entirely from intracellular choline. RESULTS: PLD2, but not PLD1, mRNA and protein were detected in these cells and endogenous PLD activity and ACh synthesis were stimulated by phorbol 12-myristate 13-acetate (PMA). Introduction of a PLD2 antisense oligonucleotide into the cells reduced PLD2 mRNA and protein expression by approximately 30%. The PLD2 antisense oligomer similarly reduced basal- and PMA-stimulated PLD activity and ACh levels. Overexpression of mouse PLD2 by transient transfection increased basal- (by 74%) and PMA-stimulated (by 3.2-fold) PLD activity. Moreover, PLD2 transfection increased ACh levels by 26% in the absence of PMA and by 2.1-fold in the presence of PMA. Overexpression of human PLD1 by transient transfection increased PLD activity by 4.6-fold and ACh synthesis by 2.3-fold in the presence of PMA as compared to controls. CONCLUSIONS: These data identify PLD2 as the endogenous enzyme that hydrolyzes PC to generate choline for ACh synthesis in cholinergic cells, and indicate that in a model system choline generated by PLD1 may also be used for this purpose.

Proteínas morfogenéticas óseas y neuronas colinérgicas en el sistema nervioso central / Bone morphogenetic proteins and cholinergic neurons in the central nervous system

Introducción. El descubrimiento de los factores que inducen y mantienen los diferentes fenotipos neuronales y sus neurotransmisores específicos tiene consecuencias clínicas importantes y continúa siendo uno de los mayores objetivos de las neurociencias. Desarrollo. Aunque se ha producido bastante progreso en esta área, todavía entendemos muy poco cómo las neuronas colinérgicas adquieren y mantienen sus características neurotransmisoras, y tampoco comprendemos muy bien cómo en algunas circunstancias éstas degeneran y pierden esta especificidad neurotransmisora. Existen datos que demuestran que algunos miembros de la familia de las proteínas morfogenéticas óseas pueden ejercer acciones profundas en la organización y diferenciación del sistema nervioso central en desarrollo, y estudios recientes indican su importante papel en la determinación del fenotipo neuronal colinérgico. Conclusiones. Las proteínas morfogenéticas óseas pueden actuar en la diferenciación de células precursoras neuronales hacia neuronas colinérgicas y, al mismo tiempo, acentuar el fenotipo colinérgico de neuronas maduras en el sistema nervioso central. Esto sugiere que estas proteínas pueden utilizarse en el tratamiento de ciertas alteraciones cerebrales en el futuro (AU)

Sex steroids modulate luteinizing hormone-releasing hormone secretion in a cholinergic cell line from the basal forebrain.

The function of a particular neuronal population is in part determined by its neurotransmitter phenotype. We have found that a neuronal-derived septal cell line (SN56), known for its cholinergic properties, also synthesizes and releases luteinizing hormone-releasing hormone. In addition, these cells express the messenger RNAs encoding estrogen and progesterone receptors. The activation of these receptors by their respective ligands cooperatively modulates the depolarization-induced release of luteinizing hormone-releasing hormone in these cells. We have also found that a number of septal neurons in postnatal (1-week-old) mice are immunoreactive to both choline acetyltransferase and luteinizing hormone-releasing hormone. These results indicate that both neurotransmitters, acetylcholine and luteinizing hormone-releasing hormone, may co-exist in septal neurons of the CNS and that they could be modulated by gonadal hormones, and suggest that luteinizing hormone-releasing hormone could be involved in some of the actions of sex steroids on cholinergic neurotransmission.

[Bone morphogenetic proteins and cholinergic neurons in the central nervous system]. / Proteínas morfogenéticas óseas y neuronas colinérgicas en el sistema nervioso central.

INTRODUCTION: The discovery and characterization of factors that induce and maintain specific neurotransmitter phenotypes has profound clinical implications, and continues to be one of the major objectives in the neurosciences. DEVELOPMENT: Although much progress has been realized in this area, we still understand little of how cholinergic neurons acquire and maintain their neurotransmitter characteristics, nor do we fully comprehend why these neurons in some circumstances degenerate and loose their neurotransmitter specificity. There is evidence that some members of the bone morphogenetic protein (BMP) family have profound organizing and differentiating actions in the developing nervous system, and recent studies indicate an important role in determining the cholinergic neuronal phenotype. CONCLUSIONS: BMP may act to differentiate neuronal precursor cells into cholinergic neurons and upregulate the cholinergic phenotype of already differentiated neurons in the central nervous system. This could suggest their potential use in the treatment of certain types of brain disorders.

Protective effects of prenatal choline supplementation on seizure-induced memory impairment.

Choline is an essential nutrient for rats and humans, and its availability during fetal development has long-lasting cognitive effects (Blusztajn, 1998). We investigated the effects of prenatal choline supplementation on memory deficits associated with status epilepticus. Pregnant rats received a control or choline-supplemented diet during days 11-17 of gestation. Male offspring [postnatal day 29 (P29)-32] were tested for their ability to find a platform in a water maze before and after administration of a convulsant dose of pilocarpine at P34. There were no differences between groups in water maze performance before the seizure. One week after status epilepticus (P41-P44), animals that had received the control diet prenatally had a drastically impaired performance in the water maze during the 4 d testing period, whereas prenatally choline-supplemented rats showed no impairment. Neither the seizures nor the prenatal availability of choline had any effect on hippocampal choline acetyltransferase or acetylcholinesterase activities. This study demonstrates that prenatal choline supplementation can protect rats against memory deficits induced by status epilepticus.

Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer's disease.

Brain cells in Alzheimer's disease (AD) exhibit a membrane defect characterized by accelerated phospholipid turnover. The mechanism responsible for this defect remains unknown. Recent studies indicate that impairment of mitochondrial function is frequently observed in AD and may be responsible for certain aspects of its pathophysiology. We show that when PC12 cells are exposed to inhibitors of mitochondrial bioenergetics, the turnover of their major membrane phospholipid, phosphatidylcholine, is accelerated, producing a pattern of metabolic changes that mimics that observed in brains of AD patients. Abnormalities of mitochondrial function may therefore underlie the membrane defect in AD.

Prenatal choline exposure alters hippocampal responsiveness to cholinergic stimulation in adulthood.

Manipulation of dietary choline levels during gestation results in enduring neurobehavioral changes in offspring that last into adulthood. Alterations of hippocampal function and memory are among the most striking changes. Depending upon the measures assessed, prenatal choline supplementation tends to promote excitatory synaptic efficacy in hippocampal circuits while prenatal choline deficiency diminishes it. However, the mechanisms underlying these changes remain unclear. Transverse hippocampal slices were prepared from adult offspring of dams fed choline supplemented, choline deficient, or control diets. We assessed paired-pulse inhibition, and excitatory synaptic responsiveness before and after activation of cholinergic receptors with Carbachol. Prenatally choline deficient animals yielded significantly fewer electrophysiological viable hippocampal slices than did animals from either of the other two treatment groups. Among the slices tested, there were no differences in paired pulse inhibition between the treatment groups. However, transient cholinergic activation resulted in a prolonged enhancement of the amplitude of the population EPSP (pEPSP) response in slices from prenatally choline supplemented animals. These results suggest that GABA receptor-mediated inhibition remains intact after prenatal choline manipulations, and that enhancement of the excitatory responsiveness of hippocampal circuits in slices from prenatally choline supplemented rats may be related in part to an increase in cholinergic tone within the CA1 circuit.

Cholinergic differentiation triggered by blocking cell proliferation and treatment with all-trans-retinoic acid.

This study determined whether the effect of all-trans-retinoic acid (t-RA) on markers of cholinergic differentiation in a murine septal cell line, SN56.B5.G4, differed depending upon the cell's proliferative status. To develop a model of non-proliferating cells, aphidicolin, a DNA alpha-polymerase inhibitor, was used. Cessation of proliferation by aphidicolin increased intracellular choline and acetylcholine (ACh) levels in the absence of change to choline acetyltransferase (ChAT) activity and mRNA and vesicular ACh transporter (VAChT) mRNA. Importantly, the response to t-RA differed depending upon proliferative status. Consistent with previous reports, t-RA increased ChAT and VAChT mRNA, ChAT activity and intracellular ACh levels in proliferating SN56 cells with no effect on intracellular choline levels. When cells were treated with t-RA while undergoing proliferative arrest, an additive effect of combined treatment was observed on ACh levels; nevertheless, this was only accompanied by an increase in choline levels, VAChT and ChAT mRNAs, but not ChAT activity. Indeed, aphidicolin treatment completely suppressed the t-RA-induced increase in ChAT activity observed in proliferating cells. To explore the response to t-RA in post-mitotic cells, a sequential treatment of aphidicolin and t-RA was employed. t-RA treatment was ineffective in increasing ACh and choline levels, over and above that observed with the aphidicolin treatment alone. Comparable to the combined treatment, sequential treatment lead to an increase in ChAT mRNA without any increase in ChAT activity. In conclusion, both the magnitude and the mechanism(s) of action whereby t-RA enhances the cholinergic phenotype of SN56 cells is dependent upon the cell's proliferative status.

Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9.

Bone morphogenetic proteins (BMPs) have multiple functions in the developing nervous system. A member of this family, BMP-9, was found to be highly expressed in the embryonic mouse septum and spinal cord, indicating a possible role in regulating the cholinergic phenotype. In cultured neurons, BMP-9 directly induced the expression of the cholinergic gene locus encoding choline acetyltransferase and the vesicular acetylcholine transporter and up-regulated acetylcholine synthesis. The effect was reversed upon withdrawal of BMP-9. Intracerebroventricular injection of BMP-9 increased acetylcholine levels in vivo. Although certain other BMPs also up-regulated the cholinergic phenotype in vitro, they were less effective than BMP-9. These data indicate that BMP-9 is a differentiating factor for cholinergic central nervous system neurons.

The cholinergic neuronal phenotype in Alzheimer's disease.

The synthesis, storage and release of acetylcholine (ACh) requires the expression of several specialized proteins, including choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). The VAChT gene is located within the first intron of the ChAT gene. This unique genomic organization permits coordinated activation of expression of the two genes by extracellular factors. Much less is known about factors that reduce the expression of the cholinergic phenotype. A cholinergic deficit is one of the primary features of Alzheimer's disease (AD), and AD brains are characterized by amyloid deposits composed primarily of A beta peptides. Although A beta peptides are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. Indeed, we and others demonstrated that synthetic A beta peptides, at submicromolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal phospholipid turnover, which might be related to the progressive accumulation of apolipoprotein E (apoE) within amyloid plaques, leading perhaps to the reduction of apoE content in the CSF of AD patients. ApoE is a component of very low density lipoproteins (VLDL). As a first step in investigating a potential neuroprotective function of apoE, we determined the effects of VLDL on ACh content in neuronal cells. We found that VLDL increases ACh levels, and that it can partially offset the anticholinergic actions of A beta peptides.

Changes in phospholipase D isoform activity and expression in multidrug-resistant human cancer cells.

Multidrug resistance (MDR) is a major cause of failure of cancer chemotherapy and is often associated with elevated expression of drug transporters such as P-glycoprotein (P-gp) in the cancer cells. MDR is, however, accompanied by additional biochemical changes including modifications of membrane composition and properties. We have shown that MDR is associated with a massive up-regulation of caveolin expression and an elevated surface density of caveolae. We report that phospholipase D (PLD), a constituent enzyme of caveolae and detergent-insoluble glycolipid-rich membranes (DIGs), is up-regulated in human MDR cancer cells. Lysates of HT-29-MDR human colon adenocarcinoma cells, MCF-7 AdrR human breast adenocarcinoma cells and the corresponding parental drug-sensitive cells, were fractionated on discontinuous sucrose density gradients. PLD activity was found to be enriched in low density fractions that contain DIGs and caveolar membranes, and the activity in these fractions was 4- to 6-fold higher in the MDR cells compared with the parental drug- sensitive cells. Utilizing specific antibodies to PLD1 and PLD2, the distribution of PLD isoforms along the gradient was determined and the PLD localized in DIGs and caveolar membranes has been identified as PLD2. Northern blot analysis of PLD1 and PLD2 mRNA levels has indicated that PLD2 mRNA is elevated in both HT-29-MDR and MCF-7 AdrR cells. PLD1 mRNA levels were either unchanged or reduced in the MDR cells. Finally, in vivo experiments have confirmed previous results showing that activation of PLD by phorbol esters is markedly potentiated in the MDR cells. We conclude that MDR is accompanied by an increase in PLD2 activity in DIGs and caveolar membranes.

Palmitoylation targets CD39/endothelial ATP diphosphohydrolase to caveolae.

Ectonucleotidases influence purinergic receptor function by the hydrolysis of extracellular nucleotides. CD39 is an integral membrane protein that is a prototype member of the nucleoside 5'-triphosphate diphosphohydrolase family. The native CD39 protein has two intracytoplasmic and two transmembrane domains. There is a large extracellular domain that undergoes extensive glycosylation and can be post-translationally modified by limited proteolysis. We have identified a potential thioester linkage site for S-acylation within the N-terminal region of CD39 and demonstrate that this region undergoes palmitoylation in a constitutive manner. The covalent lipid modification of this region of the protein appears to be important both in plasma membrane association and in targeting CD39 to caveolae. These specialized plasmalemmal domains are enriched in G protein-coupled receptors and appear to integrate cellular activation events. We suggest that palmitoylation could modulate the function of CD39 in regulating cellular signal transduction pathways.

Nutrients as trophic factors in neurons and the central nervous system: role of retinoic acid.

In multicellular organisms, death, survival, proliferation, and differentiation of a given cell depend on signals produced by neighboring and/or distant cells, resulting in the coordinated development and function of the various tissues. In the nervous system, control of cell survival and differentiation is achieved through the action of a distinct group of polypeptides collectively known as neurotrophic factors. Recent findings support the view that trophic factors also are involved in the response of the nervous system to acute injury. By contrast, nutrients are not traditionally viewed as potential trophic factors; however, there is increasing evidence that at least some influence neuronal differentiation. During development the brain is responsive to variations in nutrient supply, and this increased sensitivity or vulnerability of the brain to nutrient supply may reappear during neuronal repair, a period during which a rapid membrane resynthesis and reestablishment of synthetic pathways occur. To further evaluate the potential of specific nutrients to act as pharmacologic agents in the repair of injured neurons, the effects of retinoic acid, an active metabolite of vitamin A, and its role as a trophic factor are discussed. This literature review is intended to provide background information regarding the effect of retinoic acid on the cholinergic phenotype and the differentiation of these neurons and to explain how it may promote neuronal repair and survival following injury.

Apolipoprotein serum amyloid A down-regulates smooth-muscle cell lipid biosynthesis.

The addition of acute-phase apolipoprotein serum amyloid A (SAA) to cultured aortic smooth-muscle cells caused a decrease in the incorporation of [(14)C]acetate into lipids. Optimal inhibition of lipid biosynthesis was achieved with 2 microM SAA, and the effect was maintained for up to 1 week when SAA was included in the culture medium. Lipid extracts were subjected to TLC and it was determined that the SAA-induced decrease in [(14)C]acetate incorporation into lipids was attributable to decreases in cholesterol, phospholipid and triglyceride levels. The accumulated mass of cholesterol and phospholipid in SAA-treated cultures was significantly less than that of controls, with no change in the accumulated protein. Moreover, SAA had no effect on either protein synthesis or DNA synthesis, suggesting that SAA specifically alters lipid synthesis. By using a peptide corresponding to the cholesterol-binding domain of acute-phase SAA (amino acids 1-18), it was shown that this region of the molecule was as effective as the full-length protein in decreasing lipid synthesis and the accumulation of cholesterol and phospholipid. The implications of these findings for atherosclerosis and Alzheimer's disease are discussed.