Central Nervous System Lipid Research Articles

Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis.

GM2 gangliosidosis is a group of genetic disorders that result in the accumulation of GM2 ganglioside (GM2) in brain cells, leading to progressive central nervous system (CNS) atrophy and premature death in patients. AB-variant GM2 gangliosidosis (ABGM2) arises from loss-of-function mutations in the GM2 activator protein (GM2AP), which is essential for the breakdown of GM2 in a key catabolic pathway required for CNS lipid homeostasis. In this study, we show that intrathecal delivery of self-complementary adeno-associated virus serotype-9 (scAAV9) harbouring a functional human GM2A transgene (scAAV9.hGM2A) can prevent GM2 accumulation in in GM2AP-deficient mice (Gm2a-/- mice). Additionally, scAAV9.hGM2A efficiently distributes to all tested regions of the CNS within 14 weeks post-injection and remains detectable for the lifespan of these animals (up to 104 weeks). Remarkably, GM2AP expression from the transgene scales with increasing doses of scAAV9.hGM2A (0.5, 1.0 and 2.0 × 1011 vector genomes (vg) per mouse), and this correlates with dose-dependent correction of GM2 accumulation in the brain. No severe adverse events were observed, and comorbidities in treated mice were comparable to those in disease-free cohorts. Lastly, all doses yielded corrective outcomes. These data indicate that scAAV9.hGM2A treatment is relatively non-toxic and tolerable, and biochemically corrects GM2 accumulation in the CNS-the main cause of morbidity and mortality in patients with ABGM2. Importantly, these results constitute proof-of-principle for treating ABGM2 with scAAV9.hGM2A by means of a single intrathecal administration and establish a foundation for future preclinical research.

Ability of a Polyphenol-Rich Nutraceutical to Reduce Central Nervous System Lipid Peroxidation by Analysis of Oxylipins in Urine: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Isoprostanes (IsoPs) are lipid peroxidation biomarkers that reveal the oxidative status of the organism without specifying which organs or tissues it occurs in. Similar compounds have recently been identified that can assess central nervous system (CNS) lipid peroxidation status, usually oxidated by reactive oxygen species. These compounds are the neuroprostanes (NeuroPs) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the F2t-dihomo-isoprotanes derived from adrenic acid (AdA). The aim of the present investigation was to evaluate whether the long-term nutraceutical consumption of high polyphenolic contents (600 mg) from fruits (such as berries) and vegetables shows efficacy against CNS lipid peroxidation in urine biomarkers. A total of 92 subjects (47 females, 45 males, age 34 ± 11 years old, weight 73.10 ± 14.29 kg, height 1.72 ± 9 cm, body mass index (BMI) 24.40 ± 3.43 kg/m2) completed a randomized, cross-over, double-blind study after an intervention of two periods of 16 weeks consuming either extract (EXT) or placebo (PLA) separated by a 4-week washout period. The results showed significant reductions in three AdA-derived metabolites, namely, 17-epi-17-F2t-dihomo-IsoPs (Δ -1.65 ng/mL; p < 0.001), 17-F2t-dihomo-IsoPs (Δ -0.17 ng/mL; p < 0.015), and ent-7(RS)-7-F2t-dihomo-IsoPs (Δ -1.97 ng/mL; p < 0.001), and one DHA-derived metabolite, namely, 4-F4t-NeuroP (Δ -7.94 ng/mL; p < 0.001), after EXT consumption, which was not observed after PLA consumption. These data seem to show the effectiveness of the extract for preventing CNS lipid peroxidation, as determined by measurements of oxylipins in urine through Ultra-High-Performance Liquid Chromatography triple quadrupole tandem mass spectrometry (UHPLC-QqQ-ESI-MS/MS).

Erythrocyte Plasma Membrane Lipid Composition Mirrors That of Neurons and Glial Cells in Murine Experimental In Vitro and In Vivo Inflammation.

Lipid membrane turnover and myelin repair play a central role in diseases and lesions of the central nervous system (CNS). The aim of the present study was to analyze lipid composition changes due to inflammatory conditions. We measured the fatty acid (FA) composition in erythrocytes (RBCs) and spinal cord tissue (gas chromatography) derived from mice affected by experimental allergic encephalomyelitis (EAE) in acute and remission phases; cholesterol membrane content (Filipin) and GM1 membrane assembly (CT-B) in EAE mouse RBCs, and in cultured neurons, oligodendroglial cells and macrophages exposed to inflammatory challenges. During the EAE acute phase, the RBC membrane showed a reduction in polyunsaturated FAs (PUFAs) and an increase in saturated FAs (SFAs) and the omega-6/omega-3 ratios, followed by a restoration to control levels in the remission phase in parallel with an increase in monounsaturated fatty acid residues. A decrease in PUFAs was also shown in the spinal cord. CT-B staining decreased and Filipin staining increased in RBCs during acute EAE, as well as in cultured macrophages, neurons and oligodendrocyte precursor cells exposed to inflammatory challenges. This regulation in lipid content suggests an increased cell membrane rigidity during the inflammatory phase of EAE and supports the investigation of peripheral cell membrane lipids as possible biomarkers for CNS lipid membrane concentration and assembly.

Remarkable consistency of spinal cord microvasculature in highly adapted diving odontocetes.

Odontocetes are breath-hold divers with a suite of physiological, anatomical, and behavioral adaptations that are highly derived and vastly different from those of their terrestrial counterparts. Because of these adaptations for diving, odontocetes were originally thought to be exempt from the harms of nitrogen gas embolism while diving. However, recent studies have shown that these mammals may alter their dive behavior in response to anthropogenic sound, leading to the potential for nitrogen supersaturation and bubble formation which may cause decompression sickness in the central nervous system (CNS). We examined the degree of interface between blood, gases, and neural tissues in the spinal cord by quantifying its microvascular characteristics in five species of odontocetes (Tursiops truncatus, Delphinus delphis, Grampus griseus, Kogia breviceps, and Mesoplodon europaeus) and a model terrestrial species (the pig-Sus scrofa domesticus) for comparison. This approach allowed us to compare microvascular characteristics (microvascular density, branching, and diameter) at several positions (cervical, thoracic, and lumbar) along the spinal cord from odontocetes that are known to be either deep or shallow divers. We found no significant differences (p < 0.05 for all comparisons) in microvessel density (9.30-11.18%), microvessel branching (1.60-2.12 branches/vessel), or microvessel diameter (11.83-16.079µm) between odontocetes and the pig, or between deep and shallow diving odontocete species. This similarity of spinal cord microvasculature anatomy in several species of odontocetes as compared to the terrestrial mammal is in contrast to the wide array of remarkable physio-anatomical adaptations marine mammals have evolved within their circulatory system to cope with the physiological demands of diving. These results, and other studies on CNS lipids, indicate that the spinal cords of odontocetes do not have specialized features that might serve to protect them from Type II DCS.

Lipid Metabolism in Neurocognitive Disorders: Current Update

The physiology and the pathology of the Central Nervous System (CNS) is very complex, and only by understanding it the scientific research might develop effective treatments. Neurocognitive Disorders, extremely diffused diseases, have a multifactorial aetiology, in which lipid homeostasis plays an important role, as known. The aim of this mini-review is focus on interesting recently published researches on the topic, in order to put together some pieces of the puzzle of such an enormous physiopathology chapter. After a brief introduction, we will describe important aspects of CNS lipid metabolism, then we will examine the conclusions of recent articles relating to lipid role in neurodegeneration. The recent scientific literature has strengthened the position of some well-known “biological agents” – i.e. lipid peroxidation and apolipoprotein E4 allele –but also detailed the importance of new promising diagnostic and therapeutic targets.

Neuron-Specific Deletion of Peroxisome Proliferator-Activated Receptor Delta (PPARδ) in Mice Leads to Increased Susceptibility to Diet-Induced Obesity

Central nervous system (CNS) lipid accumulation, inflammation and resistance to adipo-regulatory hormones, such as insulin and leptin, are implicated in the pathogenesis of diet-induced obesity (DIO). Peroxisome proliferator-activated receptors (PPAR α, δ, γ) are nuclear transcription factors that act as environmental fatty acid sensors and regulate genes involved in lipid metabolism and inflammation in response to dietary and endogenous fatty acid ligands. All three PPAR isoforms are expressed in the CNS at different levels. Recent evidence suggests that activation of CNS PPARα and/or PPARγ may contribute to weight gain and obesity. PPARδ is the most abundant isoform in the CNS and is enriched in the hypothalamus, a region of the brain involved in energy homeostasis regulation. Because in peripheral tissues, expression of PPARδ increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPARδ protects against the development of DIO. Indeed, genetic neuronal deletion using Nes-Cre loxP technology led to elevated fat mass and decreased lean mass on low-fat diet (LFD), accompanied by leptin resistance and hypothalamic inflammation. Impaired regulation of neuropeptide expression, as well as uncoupling protein 2, and abnormal responses to a metabolic challenge, such as fasting, also occur in the absence of neuronal PPARδ. Consistent with our hypothesis, KO mice gain significantly more fat mass on a high-fat diet (HFD), yet are surprisingly resistant to diet-induced elevations in CNS inflammation and lipid accumulation. We detected evidence of upregulation of PPARγ and target genes of both PPARα and PPARγ, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARδ in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.

Physical and Physicochemical Factors Effecting Transport of Chlorohydrocarbon Gases from Lung Alveolar Air to Blood as Measured by the Causation of Narcosis

This systematic investigation examines gas transport in the lung for two sets of chlorohydrocarbons (CHCs): the chloromethanes (C1) and chloroethanes (C2). The C1 series includes chloromethane, methylene chloride, chloroform, and carbon tetrachloride, and the C2 series includes chloroethane, 1,2-dichloroethane, 1, 1, 2-trichloroethane, and 1, 1, 2, 2-tetrachloroethane. Most CHC gases cause narcosis. The comprehensive narcosis work of Lehmann and colleagues on CHCs was used as a basis for the narcosis endpoint in the present examination [1]. The sites for narcosis are located in the brain (midline cortex and posterior parietal area), the spine, and at many peripheral nerve sites. Central nervous system (CNS) exposure executes a multisite, neural transmission set of inhibitions that promotes rapid loss of consciousness, sensory feeling, and current and stored memory while providing temporary amnesia. Absorption into the system requires dissolution into many lipid membranes and binding to lipoproteins. Lipophilicity is a CHC property shared with many anesthetics according to the Meyer-Overton Rule. Many structurally different lipid chemicals produce the narcosis response when the lipid concentration exceeds ∼67 mM. This suggests narcotic or anesthetic dissolution into CNS membranes until the lipid organization is disrupted or perturbed. This perturbation includes loading of Na+- and K+-channel transmembrane lipoprotein complexes and disrupting their respective channel functional organizations. The channel functions become attenuated or abrogated until the CHC exposure ceases and CHC loading reverses. This investigation demonstrates how the CHC physical and chemical properties influence the absorption of these CHCs via the lung and the alveolar system on route to the blood. Narcosis in test animals was used here as an objective biological endpoint to study the effects of the physical factors Bp, Vp, Kd (oil: gas) partition, Henry's constant (HK), and water solubility (S%) on gas transport. Narcosis is immediate after gas exposure and requires no chemical activation only absorption into the blood and circulation to CNS narcotic sites. The three physical factors Bp, Kd (oil: air), and S% vary directly with unitary narcosis (UN) whereas Vp and HK vary inversely with UN in linear log-log relationships for the C2 series but not for the C1 series. Physicochemical properties of C1 series gases indicate why they depart from what is usually assumed to be an Ideal Gas. An essential discriminating process in the distal lung is the limiting alveolar film layer (AFL) and the membrane layer of the alveolar acini. The AFL step influences gas uptake by physically limiting the absorption process. Interaction with and dissolution into aqueous solvent of the AFL is required for transport and narcotic activity. Narcotics or anesthetics must engage the aqueous AFL with sufficient strength to allow transport and absorption for downstream CNS binding. CHCs that do not engage well with the AFL are not narcotic. Lipophilicity and amphipathicity are also essential solvency properties driving narcotics’ transport through the alveolar layer, delivery to the blood fats and lipoproteins, and into critical CNS lipids, lipoproteins, and receptor sites that actuate narcosis. AFL disruption is thought to be strongly related to a number of serious pulmonary diseases such acute respiratory distress syndrome, infant respiratory distress syndrome, emphysema, chronic obstructive pulmonary disease, asthma, chronic bronchitis, pneumonia, pulmonary infections, and idiopathic pulmonary fibrosis. The physical factors (Bp, Vp, Kd [oil: gas] partition, Henry's constant, and water solubility [S%]) combine to affect a specific transport through the AFL if lung C > C0 (threshold concentration for narcosis). The degree of blood CHC absorption depends on dose, lipophilicity, and lung residence time. AFL passage can be manipulated by physical factors of increased pressure (kPa) or increased gas exposure (moles). Molecular lipophilicity facilitates narcosis but lipophilicity alone does not explain narcosis. Vapor pressure is also required for narcosis. Narcotic activity apparently requires stereospecific processing in the AFL and/or down-stream inhibition at stereospecific lipoproteins at CNS inhibitory sites. It is proposed that CHCs likely cannot proceed through the AFL without perturbation or disruption of the integrity of the AFL at the alveoli. CHC physicochemical properties are not expected to allow their transport through the AFL as physiological CO2 and O2 naturally do in respiration. This work considers CHC inspiration and systemic absorption into the blood with special emphasis on the CHC potential perturbation effects on the lipid, protein liquid layer supra to the alveolar membrane (AFL). A heuristic gas transport model for the CHCs is presented as guidance for this examination. The gas transport model can be used to study absorption for other gas delivery endpoints of environmental concern such as carcinogens.

The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1

Lipoprotein metabolism in the central nervous system (CNS) is based on high-density lipoprotein-like particles that use apoE as their predominant apolipoprotein rather than apoA-I. Although apoA-I is not expressed in astrocytes and microglia, which produce CNS apoE, apoA-I is reported to be expressed in porcine brain capillary endothelial cells and also crosses the blood–brain barrier (BBB). These mechanisms allow apoA-I to reach concentrations in cerebrospinal fluid (CSF) that are approximately 0.5% of its plasma levels. Recently, apoA-I has been shown to enhance cognitive function and reduce cerebrovascular amyloid deposition in Alzheimer's Disease (AD) mice, raising questions about the regulation and function of apoA-I in the CNS. Peripheral apoA-I metabolism is highly influenced by ABCA1, but less is known about how ABCA1 regulates CNS apoA-I. We report that ABCA1 deficiency leads to greater retention of apoA-I in the CNS than in the periphery. Additionally, treatment of symptomatic AD mice with GW3965, an LXR agonist that stimulates ABCA1 expression, increases apoA-I more dramatically in the CNS compared to the periphery. Furthermore, GW3965-mediated up-regulation of CNS apoA-I is independent of ABCA1. Our results suggest that apoA-I may be regulated by distinct mechanisms on either side of the BBB and that apoA-I may serve to integrate peripheral and CNS lipid metabolism. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945–2010).

Lipidomics: The Function of Vital Lipids in Embryogenesis Preventing Autism Spectrum Disorders, Treating Sterile Inflammatory Diatheses with a Lymphopoietic Central Nervous System Component

The central role performed by billions of vital central nervous system (CNS) lipids “lipidomics” in medical physiology is usually overlooked. A metabolic deficiency embracing these vital lipids can form the aetiology for a variety of diseases. CNS lipids regulate embryogenesis, cell induction, mental balance by preventing autism spectrum disorders, depression, burn-out syndromes like posttraumatic stress disease PTSD, by guarding normal immunity, treating sterile inflammatory diatheses with a titanium containing lymphopoietic CNS lipid component. The propaganda driving for unphysiological fat-free diets is dangerous and can cause serious health problems for a whole generation. This article presents a broad list of various mental and motor bodily functions of which the healthy function depends on these vital CNS lipids. A rigorous fat-free diet can provoke these metabolic lipid deficiencies but they can fortunately be compensated by dietary supplementation, but not by pharmacologic treatment.

Effects of sub-chronic clozapine and haloperidol administration on brain lipid levels

Abnormal lipid profiles have been reported in the central nervous system (CNS) in individuals with schizophrenia, although the etiology of these changes remains to be elucidated. While treatment with second-generation antipsychotics has been associated with alterations in peripheral lipid levels and changes in erythrocyte membrane composition, the relationship between peripheral and CNS lipid levels is complex and the effect of antipsychotics on CNS lipid regulation is not yet understood. In this study we investigated whether sub-chronic administration of the second-generation antipsychotic clozapine and the first-generation antipsychotic haloperidol alters brain membrane lipid composition in male Sprague–Dawley rats. The relationship between brain membrane lipid composition and plasma cholesterol concentrations was also assessed. Our results indicate that brain lipid composition and plasma cholesterol concentrations are not altered following administration of antipsychotics. No correlation was observed between plasma and brain membrane cholesterol levels. Our findings suggest that observed alterations in brain lipid profiles in individuals with schizophrenia are not a consequence of treatment with antipsychotic medications.

Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.

Sequential pressurized liquid extraction to determine brain-originating fatty acids in meat products as markers in bovine spongiform encephalopathy risk assessment studies

A new approach using sequential pressurized liquid extraction described recently [J. Poerschmann, R. Carlson, J. Chromatogr. A, 1127 (2006) 18–25] was applied to determine lipid markers originating from central nervous system (CNS) tissue of cows in heat-processed sausages. These studies are very important in quality control as well as risk assessment studies in the face of the bovine spongiform encephalopathy (BSE) crisis. Diagnostic CNS lipid markers, which should not be present in meat products without CNS addition, were recognized on complete transesterification as polar 2-hydroxy-fatty acids (2OH-24:0, 2OH-24:1, 2OH-22:0, 2OH-18:0, shorthand designation) as well as odd-numbered non-branched fatty acids beyond C 22. An array of other fatty acids including lignoceric acid (24:0), nervonic acid (24:1), arachidonic acid (20:4), and polyunsaturated nC 22-surrogates are strongly related to CNS lipids, but occur as traces in meat products without CNS addition as well, thus reducing their value as diagnostic markers. Samples including meat products without CNS addition, meat with 3% CNS addition, as well as pure CNS homogenates, were subjected to sequential PLE (pressurized liquid extraction) consisting of two steps: n-hexane/acetone 9:1 (v/v) extraction at 50 °C to remove neutral lipids, followed by chloroform/methanol 1:4 (v/v) extraction at 110 °C to isolate polar CNS lipids (two 10 min PLE cycles each). To enhance the fractionation efficiency, cyanopropyl modified silica as well as chemically not modified silica sorbent was used at the outlet of the PLE cartridge to retard polar lipids in the first extraction step. This method proved superior to widely distributed exhaustive lipid extraction followed by solid-phase extraction (SPE) using silica regarding lipid recoveries and clear-cut boundaries between lipid classes. Methodological studies showed that the alcoholysis using trimethylchlorosilane/methanol (1:9, v/v) is an excellent method for the complete transesterification of lipids and quantitative formation of methyl esters.

Circulatory Arrest as a Model for Studies of Global Ischemic Injury and Neuroprotection

Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8-12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8-iso-PGF(2alpha)), an indicator of oxidative damage, and prostaglandin F(2alpha) metabolite (15-keto-dihydro-PGF(2alpha)), an indicator of cyclooxygenase-2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S-100beta. Neurological outcome is assessed at >24 h after the incident. Our results show that plasma concentrations of 8-iso-PGF(2alpha) are greater after more extended periods of ischemia. PBN (alpha-phenyl-N-tert-butyl nitrone), a so-called spin-trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8-iso-PGF(2alpha) concentration is decreased during reperfusion. Use of water-soluble sulfonated PBN (S-PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.

Circulatory Arrest as a Model for Studies of Global Ischemic Injury and Neuroprotection

Abstract: Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8‐12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8‐iso‐PGF2α), an indicator of oxidative damage, and prostaglandin F2α metabolite (15‐keto‐dihydro‐PGF2α), an indicator of cyclooxygenase‐2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S‐100β. Neurological outcome is assessed at &gt;24 h after the incident. Our results show that plasma concentrations of 8‐iso‐PGF2α are greater after more extended periods of ischemia. PBN (α‐phenyl‐N‐tert‐butyl nitrone), a so‐called spin‐trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8‐iso‐PGF2α concentration is decreased during reperfusion. Use of water‐soluble sulfonated PBN (S‐PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.

Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain

ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system (CNS), ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells within the CNS, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in CNS lipid metabolism. Here we demonstrate that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1-/- glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1-/- astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains of ABCA1-/- mice. Taken together, these results show that glial ABCA1 is a key influence on apoE metabolism in the CNS.

The role of apolipoprotein E in lipid metabolism in the central nervous system.

The critical roles of apolipoprotein E (apoE) in regulating plasma lipid and lipoprotein levels have been extensively studied for over 2 decades. However, an understanding of the roles of apoE in the central nervous system (CNS) is less certain. This review will summarize the available experimental results on the role of apoE in CNS lipid homeostasis with respect to its modulation of sulfatide trafficking, alteration of CNS cholesterol homeostasis and apoE-induced changes in phospholipid molecular species in specialized subcellular membrane fractions. The results indicate that apoE mediates sulfatide trafficking and metabolism in the CNS. Moreover, although apoE does not affect the cholesterol mass content or the phospholipid mass levels and composition in the CNS as a whole, apoE modulates cholesterol and phospholipid homeostasis in selective subcellular membrane compartments. Through elucidating the roles of apoE in CNS lipid metabolism, new insights into overall functions of apoE in neurobiology can be accrued ultimately, leading to an increased understanding of CNS lipid metabolism and the identification of novel therapeutic targets for CNS diseases.

Experimental autoimmune encephalomyelitis: antigen-induced inhibition of biochemical and immunohistological alterations.

A comprehensive biochemical, immunological, and histological study was undertaken during suppression of experimental autoimmune encephalomyelitis (EAE) induced by antigen-specific inhibition of the immune response. Pretreatment of Wistar rats by intraperitoneal administration of low doses of saline-soluble bovine myelin or myelin basic protein (MBP) but not with ovalbumin suppresses the appearance of the clinical symptoms of EAE induced by sensitization with bovine myelin in complete Freund's adjuvant. Analysis of the central nervous system (CNS) of animals pretreated with MBP or whole myelin shows inhibition of the diminution of MBP and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) activity observed in the EAE animals or in rats pretreated with ovalbumin. With respect to the CNS lipid content, these suppressive treatments abolish the increase in esterified cholesterol and partially revert the diminution in the content of cerebrosides and total cholesterol characteristic of the acute stage of the disease. Concomitantly, meningeal and parenchymal infiltration with mononuclear cells and deposits of immunoglobulins in the infiltrated regions as well as in spinal cord motor neurons were reduced. Analysis of the humoral response to myelin antigens shows that all EAE as well as treated animals developed antibodies to MBP and other myelin proteins. However, a higher incidence and level of these antibodies was observed in nontreated EAE animals and MBP- and ovalbumin-treated rats, while rats treated with total bovine myelin showed a highly reduced humoral response. The present results indicate that intraperitoneal treatment with soluble forms of myelin antigens, concomitant with the suppression of the clinical symptoms of the disease, markedly reduces the biochemical and histological alterations occurring in EAE animals and produces changes in the autoimmune humoral response.

Plasma and red blood cell fatty acid values as indexes of essential fatty acids in the developing organs of infants fed with milk or formulas

The dietary requirement of n-6 and n-3 fatty acids for normal biochemical and functional development of the central nervous system (CNS) is an important, unresolved issue in infant nutrition. High levels of arachidonic acid (AA; 20:4n-6) and docosahexaenoic acid (DHA; 22:6n-3) are found in the CNS and are important to normal learning and visual function. Dietary fatty acids may be desaturated and elongated to AA and DHA, respectively, but may also be oxidized for energy. Synthesis of AA and DHA in the young infant, therefore, depends on adequate desaturase enzyme activity, as well as an adequate supply of dietary 18:2n-6, 18:3n-3, and energy. Levels of AA and DHA are lower in the plasma and red blood cell (RBC) lipids of infants fed formula rather than human milk and are not increased with increased formula 18:2n-6 or 18:3n-3 supply. The decline in AA and DHA in infants fed formula becomes evident in the order plasma phospholipid greater than RBC phosphatidylcholine greater than RBC phosphatidylethanolamine. As in infants, piglets fed formula rather than natural milk have lower plasma and RBC AA and DHA concentrations. Despite lower levels in the plasma and RBC, analyses of CNS lipids demonstrated adequate AA and DHA in piglets fed formula with greater than 7% kcal 18:2n-6 and greater than 0.3% kcal 18:3n-3. This finding suggests that circulating lipid fatty acids are not specific indexes of organ deficiency. The rapid decrease in circulating lipid AA and DHA concentrations experienced by premature infants during early postnatal parenteral and enteral nutrition, however, may be related to oxidation of 18:2n-6 and 18:3n-3, rather than equilibrium of circulating lipids with the dietary fatty acids. Arachidonic acid and DHA may be conditionally essential nutrients for these infants because of oxidation of 18:2n-6 and 18:3n-3 for energy during periods of negative energy balance.

Hemoglobin-mediated oxidant damage to the central nervous system requires endogenous ascorbate.

Hemorrhage within the central nervous system (CNS) may be associated with subsequent development of seizure states or paralysis. Prior investigations indicate that hemoglobin, released from extravasated erythrocytes, may be toxic to the CNS by promoting peroxidation of lipids and inhibition of Na,K-ATPase. These deleterious effects are blocked both in vitro and in vivo by the Fe3+ chelator, desferrioxamine, indicating the involvement of free iron derived from hemoglobin. We now report that the Fe2+ chelator, ferene, also inhibits methemoglobin- and ferric iron-mediated CNS lipid oxidation, reflecting the reduction of Fe3+ by some component of the CNS. This reduction is apparent in the accumulation of the highly chromophoric ferene: Fe2+ chelate after the addition of Fe3+ salts to supernatants of murine brain homogenates. Because large amounts of ascorbic acid occur in mammalian CNS, we suspected that this reducing substance might be responsible. Indeed, the peroxidative effects of hemoglobin and iron on murine brain are blocked by washing of CNS membranes or by preincubation of crude homogenates with ascorbate oxidase. Furthermore, the addition of ascorbate to washed CNS membranes fully restores hemoglobin/iron-driven peroxidation. We conclude that posthemorrhagic CNS dysfunction may stem from damaging redox reactions between hemoglobin iron, ascorbic acid, and oxidizable components of the nervous system.

A Survey of Neurological Mutant Mice. pp 110–122

The lipids of white matter and peripheral nerve from mutant mice with known myelin deficiencies were analyzed by one- and two-dimensional high-performance thin-layer chromatography and quantitated by densitometry. In optic nerve, the mutants <i>jp</i>/Y, <i>jp</i>^msd/Y, qk/qk, <i>shi/shi</i> and <i>shi</i>^mld/<i>shi</i>^mld, which have severe central nervous system (CNS) myelin deficiency, had a common pattern of lipid loss: cerebrosides and sulfatides (hydroxy and nonhydroxy forms) were generally reduced by 70–95% or more; most phospholipids were diminished by 15–55%, and cholesterol was reduced by 35–60%. Only in the CNS of <i>jp</i>/Y and <i>jp</i>^msd/Y did cholesterol ester accumulate. In peripheral nerve, the lipid composition varied markedly among these mutants. In <i>jp</i>/Y there was no change, while in <i>jp</i>^msd/Y there was a 5–15% loss among the phospholipids and cholesterol. Homozygous <i>qk</i> had reductions of 75–85% in the nonhydroxy forms of cerebroside and sulfatide, a 130% increase in hydroxy sulfatide, and a 55% loss of sphingomyelin. In <i>shi/shi</i> and <i>shi</i>^mld/<i>shi</i>^mld homozygotes, the glycolipids were altered by ± 20%, most phospholipids and cholesterol were reduced by 5–15%, and sphingomyelin was reduced by 40%. <i>Tr</i> and <i>Tr^J</i> showed 35–90% reductions in most lipid classes of the peripheral nervous system; CNS lipid composition was normal. Homozygous <i>twi</i> had a uniform loss of most lipid classes in both optic (generally 10–20%) and trigeminal nerves (generally 40–55%); cerebrosides did not accumulate in these tissues, <i>dy/dy</i> had a 10–20% reduction of cerebrosides in trigeminal nerve trunk. The CNS of <i>dy</i> homozygotes had 10–35% increases in specific classes of glycolipids and phospholipids, and in cholesterol. None of the mutants showed detectable levels of lysophospholipids or other unusual lipid species. The fractions of ethanolamine and choline phosphatides in the plasmalogen form were close to normal in all mutants.