Lipoprotein Particles in Cerebrospinal Fluid.

The brain is the most lipid-rich organ in the body, and the intricate interplay between lipid metabolism and pathologies associated with neurodegenerative disorders is being increasingly recognized. The brain is bathed in cerebrospinal fluid (CSF), which, like plasma, contains lipid-protein complexes called lipoproteins that are responsible for extracellular lipid transport. Multiple CSF lipoprotein populations exist, some of which are produced de novo in the central nervous system and others that appear to be generated from protein constituents that are produced in the periphery. These CSF lipoproteins are thought to play key roles in maintaining lipid homeostasis in the central nervous system, while little else is known due to their limited accessibility and their low abundance in CSF. Recent work has provided new insights into the compositional complexity of CSF lipoprotein families and their metabolism in cerebral circulation. The purpose of this review is to summarize our current state of knowledge on the composition, origin, and metabolism of CSF lipoproteins.

[Lipoproteins and their receptors in the central nervous system].

Central nervous system(CNS) has nearly a quarter of total body cholesterol, although its weight is only 2% of the whole body. In the adult brain, cholesterol synthesis is extremely low, and a half life of cholesterol is about 5 years. In the cerebrospinal fluid(CSF), the only lipoprotein is high-density lipoprotein (HDL). CSF-HDL is larger than plasma HDL, and rich in apolipoprotein E (apoE). In CNS, neurons and glia cells express several lipoprotein receptors and ATP-binding cassette (ABC) transporters. These lipoprotein receptors can bind to and take up CSF-HDL for cholesterol recycling. Recent research has focused on investigating the role of CSF-HDL and lipoprotein receptors in the pathogenesis of Alzheimer disease.

WNT5A is transported via lipoprotein particles in the cerebrospinal fluid to regulate hindbrain morphogenesis.

WNTs are lipid-modified proteins that control multiple functions in development and disease via short- and long-range signaling. However, it is unclear how these hydrophobic molecules spread over long distances in the mammalian brain. Here we show that WNT5A is produced by the choroid plexus (ChP) of the developing hindbrain, but not the telencephalon, in both mouse and human. Since the ChP produces and secretes the cerebrospinal fluid (CSF), we examine the presence of WNT5A in the CSF and find that it is associated with lipoprotein particles rather than exosomes. Moreover, since the CSF flows along the apical surface of hindbrain progenitors not expressing Wnt5a, we examined whether deletion of Wnt5a in the ChP controls their function and find that cerebellar morphogenesis is impaired. Our study thus identifies the CSF as a route and lipoprotein particles as a vehicle for long-range transport of biologically active WNT in the central nervous system.

Soluble LR11 competes with amyloid ß in binding to cerebrospinal fluid-high-density lipoprotein.

BACKGROUND: LR11 is a member of the low-density lipoprotein (LDL) receptor family with high expression in neurons. Some cell surface LR11 is cleaved and secreted into the cerebrospinal fluid (CSF) as soluble LR11 (sLR11). Patients with Alzheimer's disease (AD), particularly apolipoprotein E4 carriers, have high CSF-sLR11 and low CSF-amyloid ß (Aß) concentrations. Therefore, we assessed whether sLR11 is bound to CSF-high-density lipoprotein (HDL) and whether sLR11 competes with Aß in binding to apoE in CSF-HDL. METHODS: We measured CSF-sLR11 concentrations (50 controls and 16 patients with AD) using enzyme immunoassay. sLR11 and apoE distribution in the CSF was evaluated using non-denaturing two-dimensional gel electrophoresis (N-2DGE). ApoE bound to sLR11 or Aß was identified using co-immunoprecipitation assay. RESULTS: CSF-sLR11 concentrations were higher in patients with AD than controls (adjusted for sLR11 using phospholipid). N-2DGE analysis showed that sLR11 and Aß comigrated with a large apoE-containing CSF-HDL. Moreover, fewer apoE was bound to Aß when a higher amount of apoE was bound to sLR11 in patients with AD who presented with ε4/4. CONCLUSION: sLR11 binds to CSF-HDL and competes with Aß in binding to apoE in CSF-HDL, indicating that sLR11 affects Aß clearance via CSF-HDL.

Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid.

The aim of the present study was to define lipoprotein complexes within cerebrospinal fluid (CSF) in terms of their apolipoprotein composition, using fractionation procedures considered optimal for maintaining lipoprotein structural integrity. Five apolipoproteins were identified, namely apolipoproteins A-I, A-IV, D, E and J. These were differentially distributed amongst lipoprotein particles of which three major subpopulations were identified. CSF-LpAI (20.1 +/- 3.8 nm) was enriched in apolipoprotein A-I and contained the major proportion (> 50%) of apolipoproteins D, E and J. CSF-LpE, of similar size to CSF-LpAI (20.2 +/- 3.1 nm), was composed principally of apolipoprotein E, with minor quantities of apolipoproteins A-I, A-IV, D and J. Elimination of these particles from cerebrospinal fluid by immunoabsorption revealed a third subpopulation of significantly greater diameter (32.0 +/- 6.8 nm). The majority (62%) of apolipoprotein A-IV was also present in this fraction. The study demonstrates the structural and size heterogeneity of lipoproteins in cerebrospinal fluid. This may reflect the lipid transport processes within the central nervous system.

Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma.

Amyloid-beta (Abeta) peptide, a major constituent of senile plaques and a hallmark of Alzheimer's disease (AD), is normally secreted by neurons and can be found in low concentrations in cerebrospinal fluid (CSF) and plasma, where it is associated with lipoproteins. However, the physiological role of Abeta secretion remains unknown. Here we show that at the concentrations measured in biological fluids (0.1-1.0 nM), Abeta(1-40) strongly inhibits autooxidation of CSF lipoproteins and plasma low density lipoprotein (LDL). At higher concentrations of the peptide its antioxidant action was abolished. Abeta(1-40) also inhibited copper-catalyzed LDL oxidation when added in molar excess of copper, but did not influence oxidation induced by an azo-initiator. Other Abeta peptides also possessed antioxidant activity in the order Abeta(1-40) > Abeta(1-42) > Abeta(25-35), whereas Abeta(35-25) was inactive. These data suggest that Abeta(1-40) may act as a physiological antioxidant in CSF and plasma lipoproteins, functioning by chelating transition metal ions.

Increased lipoprotein oxidation in Alzheimer's disease.

Oxidation has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and amyloid beta is considered to induce oxidation. In biological fluids, including cerebrospinal fluid (CSF), amyloid beta is found complexed to lipoproteins. On the basis of these observations, we investigated the potential role of lipoprotein oxidation in the pathology of AD. Lipoprotein oxidizability was measured in vitro in CSF and plasma from 29 AD patients and found to be significantly increased in comparison to 29 nondemented controls. The levels of the hydrophilic antioxidant ascorbate were significantly lower in CSF and plasma from AD patients. In plasma, alpha-carotene was significantly lower in AD patients compared to controls while alpha-tocopherol levels were indistinguishable between patients and controls. In CSF, a nonsignificant trend to lower alpha-tocopherol levels among AD patients was found. Polyunsaturated fatty acids, the lipid substrate for oxidation, were significantly lower in the CSF of AD patients. Our findings suggest that (i) lipoprotein oxidation may be important in the development of AD and (ii) the in vitro measurement of lipid peroxidation in CSF might become a useful additional marker for diagnosis of AD.

Remodelling of cerebrospinal fluid lipoproteins after subarachnoid hemorrhage.

Lipoprotein particles (Lps) in normal human cerebrospinal fluid (CSF) are distinct from those found in plasma and include unique apolipoprotein E (apoE indicates protein; APOE, gene) containing lipoproteins rarely seen in human plasma. Less favourable neurological recovery after subarachnoid hemorrhage (SAH) has been observed in patients who possess the APOE epsilon4 allele raising the possibility that apoE influences neuronal survival after brain injury. We analysed Lps from control and SAH CSF testing the hypotheses that following brain injury CSF Lps undergo remodelling and apoE containing Lps are selectively depleted from brain injury CSF. Lipoproteins were fractionated using CSF from six control pools and six patients with SAH on a sepharose 6HR 10/30 size exclusion column. Fractions were assayed for total cholesterol (TC), free cholesterol (FC), phospholipid, triglyceride (TG), apoE, apolipoprotein B (apoB), and apolipoprotein AI (apoAI). Compared to control CSF there were significant (P<0.05) increases in TC, FC, TG, and apoAI in SAH CSF. Plasma sized apoB-containing lipoproteins and a very small apoAI-containing Lps were identified in the SAH CSF, which were not present in controls. However, despite the release of plasma lipoproteins into the subarachnoid space, there was no significant increase in CSF apoE. These data provide novel indirect evidence suggesting that after SAH CSF Lps undergo remodelling and apoE containing Lps are selectively reduced in brain injury CSF. The remodelling of CSF Lps and selective reduction of apoE containing lipoproteins may reflect an important response of the human brain to injury.

Brain lipoprotein metabolism and its relation to neurodegenerative disease.

Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these complexes is to provide cells of the organism with lipids to be used as a source of energy, building blocks for biomembrane synthesis, and lipophilic molecules (e.g., steroid hormones and vitamin E) for other physiological purposes, such as cell signaling and antioxidative mechanisms. Lipoproteins also promote the cellular efflux of cholesterol for its disposal into bile. Thus, lipoproteins play an important role in the maintenance of lipid homeostasis throughout the organism. Accordingly, lipoprotein particles have been found circulating in blood, lymph, and interstitial fluid. Despite the existence of the blood-brain barrier, lipoprotein particles have been shown to be also present in the cerebrospinal fluid (CSF). Although a portion of their protein components may filter through the barrier from the vascular compartment, experimental evidence indicates that these particles originate from the nervous tissue. The other protein components include apolipoproteins E, J, and D, and these have been shown to be synthesized by cells within the central nervous system (CNS). Furthermore, it was shown that lipoprotein particles can be isolated from the conditioned medium of astrocytic cultures. The differences in size, structure, and composition of in vitro assembled particles compared with those isolated from the CSF suggest that the particles are modified following their secretion in vivo. This is supported by observations that lipoprotein-modifying enzymes and transfer proteins are also present within CNS tissue and CSF. The fate of CSF lipoproteins is unclear but is probably related to the turnover and clearance of lipids from the CNS or, alternatively, the particles may be recaptured and recycled back into the CNS tissue. The presence of several cell surface receptors for apoE-containing lipoproteins on ependymal cells, as well as on neurons and glial cells, supports this notion and suggests that the isolated brain possesses its own system to maintain local lipid homeostasis. This is further exemplified by the salvage and recycling of lipids shown to occur following a lesion in order to allow surviving neurons to sprout and reestablish lost synapses. Not much is currently known about lipoprotein metabolism in neurodegenerative diseases, but lipid alterations have been repeatedly reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Although the mechanism underlying the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer's disease is presently unclear, it may well be postulated that it is related to disturbances in brain lipoprotein metabolism.

Cerebrospinal fluid lipoprotein delivery to human neuronal cells is increased in Alzheimer's disease and is dependent on apoE monomer concentration.

Recent studies of cerebrospinal fluid (CSF) have shown increased oxidation of CSF lipoproteins in Alzheimer's disease (AD) patients, and neurotoxicity from oxidized CSF lipoproteins in culture. Since inheritance of different alleles of the apolipoprotein (apo) E gene is a risk factor for AD and apoE is the major lipoprotein trafficking molecule in brain, we hypothesized that apoE may modify the pathogenesis of AD by directing the delivery of oxidized CSF lipoproteins to neurons. To test this hypothesis, we adapted a method previously used with isolated plasma lipoproteins to specifically label lipid particles in situ in native CSF and quantified their delivery to human SK-N-BE(2)C neuroblastoma cells. CSF lipoproteins were delivered to neuronal cells largely through apoE-dependent processes. Importantly, CSF lipoproteins from AD patients were delivered more efficiently than CSF lipoproteins from age-matched controls; this effect was not associated with apoE genotype or degree of CSF lipoprotein oxidation but was associated with apoE monomer concentration that tended to be lower in AD patients. The inverse relationship between apoE monomer concentration and CSF lipoprotein delivery was duplicated in SK-N-BE(2)C cells, but not human astrocytoma cells, using artificial lipid particles and purified human apoE. These results suggest that lipoproteins in CSF from AD patients are delivered more efficiently to neurons than are CSF lipoproteins from controls, and that this abnormality may be explained largely by variations in CSF apoE concentration.

Metabolic disturbances in Plasmodium coatneyi-infected rhesus monkeys.

To investigate metabolic disturbances in an animal model of human malaria, four rhesus monkeys (Macaca mulatta) were infected with Plasmodium coatneyi, a parasite which induces cytoadherence of infected erythrocytes. When moribund or the parasitaemia had plateaued, the monkeys were sacrificed (3 animals) or treated with chloroquine (1 animal). Blood and cerebrospinal fluid (CSF) were sampled at intervals between inoculation and sacrifice or treatment. Arterial and CSF glucose and lactate rose during infection, indicating evolving insulin resistance. The arteriovenous difference in glucose concentration also increased, consistent with increased glucose consumption by parasitised tissues. Arterial plasma lactate rose but a positive arteriovenous concentration difference suggested tissue lactate uptake. The animal with the highest plasma lactate at sacrifice remained hyperglycaemic but also had the highest CSF lactate, the greatest cerebral sequestration and neurological depression, and biochemical and histological evidence of severe hepatic pathology. Serum cholesterol and corrected serum calcium fell consistently during infection; serum phosphate was also reduced in animals without renal impairment. These preliminary results indicate that lactic acidosis is a late complication of severe malaria and, by implication from this and other studies, hypoglycaemia occurs even later; other metabolic changes during P. coatneyi infection in rhesus monkeys also parallel those of severe falciparum malaria in humans. The model could be used in further studies of malaria-associated metabolic dysfunction and its management.

Remodeling of cerebrospinal fluid lipoprotein particles after human traumatic brain injury.

The association between possession of the APOE epsilon4 allele and unfavourable outcome after traumatic brain injury (TBI) suggests that the apolipoprotein E protein (apoE) plays a key role in the response of the human brain to injury. ApoE is known to regulate cholesterol metabolism in the periphery through its action as a ligand for receptor mediated uptake of lipoprotein particles (Lps). Greater understanding of cholesterol metabolism in the human central nervous system may identify novel treatment strategies applicable to acute brain injury. We report findings from the analysis of lipoproteins in the cerebrospinal fluid (CSF) of patients with TBI and non-injured controls, testing the hypothesis that remodeling of CSF lipoproteins reflects the response of the brain to TBI. CSF Lps were isolated from the CSF of controls and patients with severe TBI by size exclusion chromatography, and the lipoprotein fractions analysed for cholesterol, phospholipid, apoAI, and apoE. There was a marked decrease in apoE containing Lps in the TBI CSF compared to controls (p=0.002). After TBI there was no significant decrease in apoAI containing CSF Lps (CSF LpAI), but the apoAI resided on smaller sized particles than in control CSF. There was a population of very small sized Lps in TBI CSF, which were associated with the increased cholesterol (p=0.0001) and phospholipid (p=0.040) seen after TBI. The dramatic loss of apoE containing Lps from the CSF, and the substantial increase in CSF cholesterol, support the concept that apoE and cholesterol metabolism are intimately linked in the context of acute brain injury. Treatment strategies targeting CNS lipid transport, required for neuronal sprouting and synaptogenesis, may be applicable to traumatic brain injury.

Lipoproteins in the central nervous system.

Although the synthesis and metabolism of plasma lipoproteins are well characterized, little is known about lipid delivery and clearance within the central nervous system (CNS). Our work has focused on characterizing the lipoprotein particles present in the cerebrospinal fluid (CSF) and the nascent particles secreted by astrocytes. In addition to carrying lipids, we have found that beta-amyloid (A beta) associates with lipoproteins, including the discoidal particles secreted by cultured astrocytes and the spherical lipoproteins found in CSF. We believe that association with lipoproteins provides a means of transport and clearance for A beta. This process may be further influenced by an interaction between A beta and apoprotein E (apoE), the primary protein component of CNS lipoproteins. Specifically, we have investigated the formation and physiologic relevance of a SDS-stable complex between apoE and A beta. In biochemical assays, native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with A beta that is 20-fold more abundant than the apoE4:A beta complex. In cell culture, native apoE3 but not E4 prevents A beta-induced neurotoxicity by a mechanism dependent on cell surface apoE receptors. In addition, apoE and the inhibition of apoE receptors prevent A beta-induced astrocyte activation. Therefore, we hypothesize that the protection from A beta-induced neurotoxicity afforded by apoE3 may result from clearance of the peptide by SDS-stable apoE3:A beta complex formation and uptake by apoE receptors.

Vitamin E in neurodegenerative disorders: Alzheimer's disease.

Oxidative stress is important in the pathogenesis of Alzheimer's disease (AD). The brain contains high levels of oxidizable lipids that must be protected by antioxidants. Low concentrations of vitamin E, quantitatively the major lipophilic antioxidant in the brain, are frequently observed in cerebrospinal fluid (CSF) of AD patients, suggesting that supplementation with vitamin E might delay the development of AD. In a placebo-controlled trial, vitamin E (2000 IU/day, 2 years) slowed (-53%) functional deterioration in patients with moderate AD (Sano et al., N. Engl. J. Med. 336: 1216-1222, 1997). Recently, use of vitamin E and vitamin C supplements in combination was found to be associated with reduced prevalence (-78%) and incidence (-64%) of AD in elderly population (Zandi et al., Arch. Neurol. 61: 82-88, 2004). These results are consistent with the ability of the supplementation with vitamin E (400 IU/day, 1 month) to increase its levels in CSF (123%) and plasma (145%) of AD patients and, in combination with vitamin C (1000 g/day), to decrease the susceptibility of CSF lipoproteins (up to -32%) to in vitro oxidation (Kontush et al., Free Radic. Biol. Med. 31: 345-354, 2001). In addition, vitamin E reduced lipid peroxidation and amyloid deposition in a transgenic mice model of AD (Sung et al., FASEB J. 18: 323-325, 2004). Computer modeling of the influence of vitamin E on lipoprotein oxidation reveals that the vitamin develops antioxidative activity in CSF lipoproteins in the presence of physiologically relevant, low amounts of oxidants. By contrast, under similar conditions, vitamin E behaves as a pro-oxidant in plasma lipoproteins, consistent with the model of tocopherol-mediated peroxidation (Stocker, Curr. Opin. Lipidol. 5: 422-433, 1994). This distinction is related to major differences in the levels of vitamin E (50 nM vs. 30 microM) and oxidizable lipids (4 microM vs. 2.5 mM) between CSF and plasma, which result in major differences in oxidative conditions (per unit of vitamin E) between CSF and plasma in the presence of similar amounts of oxidants. Altogether, these data suggest that vitamin E may be effective against in vivo oxidation of CSF lipoproteins and brain lipids, and offer new perspectives in the treatment of AD and other neurodegenerative disorders.

Cerebrospinal fluid lipoproteins in Alzheimer's disease.

Interest in cerebrospinal fluid (CSF) lipoproteins has been stimulated by the association of certain alleles of the human apolipoprotein E gene (APOE) with an increased risk of Alzheimer's disease (AD), and because apolipoprotein E (apoE) is one of the major apolipoproteins in CSF. CSF lipoproteins (d < 1.210 g/ml fraction) are distinct from their plasma counterparts, and in AD patients CSF may contain novel particles. The protein concentration of CSF lipoproteins is reduced in AD patients. Moreover, the molecular distribution of apoE- and apoAII-containing apolipoproteins in CSF is dictated by APOE. The lipid composition suggests that CSF lipoproteins from AD patients may have undergone increased free radical-mediated damage; experimental data support the possibility that this may occur both before and after lipoprotein assembly. Finally, human CSF lipoproteins oxidized ex vivo are neurotoxic to neuronal cells in culture and disrupt microtubule structure, an activity not observed with oxidized bovine CSF lipoproteins. CSF lipoproteins may represent a means whereby apoE influences the outcome of free radical-mediated damage to brain.

Resistance of human cerebrospinal fluid to in vitro oxidation is directly related to its amyloid-beta content.

Amyloid-beta (A beta) peptide, a major constituent of senile plaques and a hallmark of Alzheimer's disease (AD), is normally secreted by neurons and can be found in low concentrations in cerebrospinal fluid (CSF) and plasma where it is associated with lipoproteins. However, the physiological role of A beta secretion remains unknown. We measured the resistance to in vitro oxidation of CSF obtained from 20 control subjects and 30 patients with AD, and correlated it with CSF levels of antioxidants, lipids and A beta. We found that the oxidative resistance, expressed as a duration of the oxidation lag-phase, was directly related to CSF levels of A beta 1-40, A beta 1-42 and ascorbate and inversely to levels of fatty acids. These data suggest that, besides ascorbate, A beta is another major physiological antioxidant for CSF lipoproteins.

Time-course of oxidation of lipids in human cerebrospinal fluid in vitro.

Oxidative mechanisms play an important role in the pathogenesis of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. To assess whether the oxidation of brain lipoproteins plays a role in the development of these pathologies, we investigated whether the lipoproteins of human cerebrospinal fluid (CSF) are susceptible to oxidative modification in vitro. We studied oxidation time-course for up to 100 h of human CSF in the absence (autooxidation) or presence of exogenous oxidants. Autooxidation of diluted CSF was found to result in a slow accumulation of lipid peroxidation products. The time-course of lipid hydroperoxide accumulation revealed three consecutive phases, lag-phase, propagation phase and plateau phase. Qualitatively similar time-course has been typically found in human plasma and plasma lipoproteins. Autooxidation of CSF was accelerated by adding exogenous oxidants, delayed by adding antioxidants and completely inhibited by adding a chelator of transition metal ions. Autooxidation of CSF also resulted in the consumption of endogenous ascorbate, alpha-tocopherol, urate and linoleic and arachidonic acids. Taking into account that (i) lipid peroxidation products measured in our study are known to be derived from fatty acids, and (ii) lipophilic antioxidants and fatty acids present in CSF are likely to be located in CSF lipoproteins, we conclude that lipoproteins of human CSF are modified in vitro during its autooxidation. This autooxidation appears to be catalyzed by transition metal ions, such as Cu(II) and Fe(III), which are present in native CSF. These data suggest that the oxidation of CSF lipoproteins might occur in vivo and play a role in the pathogenesis of neurodegenerative diseases.

Human, but not bovine, oxidized cerebral spinal fluid lipoproteins disrupt neuronal microtubules.

Cerebral spinal fluid (CSF) lipoproteins have become a focus of research since the observation that inheritance of particular alleles of the apolipoprotein E gene affects the risk of Alzheimer's disease (AD). There is evidence of increased lipid peroxidation in CSF lipoproteins from patients with AD, but the biological significance of this observation is not known. A characteristic of the AD brain is a disturbance of the neuronal microtubule organization. We have shown previously that 4-hydroxy-2(E)-nonenal, a major product of lipid peroxidation, causes disruption of neuronal microtubules and therefore tested whether oxidized CSF lipoproteins had the same effect. We exposed Neuro 2A cells to human CSF lipoproteins and analyzed the microtubule organization by immunofluorescence. In vitro oxidized human CSF lipoproteins caused disruption of the microtubule network, while their native (nonoxidized) counterparts did not. Microtubule disruption was observed after short exposures (1 h) and lipoprotein concentrations were present in CSF (20 microg/mL), conditions that did not result in loss of cell viability. Importantly, adult bovine CSF lipoproteins, oxidized under identical conditions, had no effect on the microtubule organization of Neuro 2A cells. Comparison of human and bovine CSF lipoproteins revealed similar oxidation-induced modifications of apolipoproteins E and A-I as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Fatty acid analysis revealed substantially lower amounts of unsaturated fatty acids in bovine CSF lipoproteins, when compared to their human counterparts. Our data therefore indicate that oxidized human CSF lipoproteins are detrimental to neuronal microtubules. This effect is species-specific, since equally oxidized bovine CSF lipoproteins left the neuronal microtubule organization unchanged.

CSF lipoproteins and Alzheimer's disease.

Alterations in lipid homeostasis have been suggested to play a role in the pathogenesis of Alzheimer's disease (AD). This hypothesis is supported by the observed changes in lipid content and composition of AD brains when compared to age-matched control brains. The association between the e4 allele of the apolipoprotein E gene and increased risk of AD implicates lipoproteins in the pathogenesis. Lipoproteins are macromolecular particles responsible for lipid trafficking and metabolism. CNS lipoproteins are different from their plasma counter parts. We review the current understanding of the structure and functions of CNS lipoproteins. In addition to mediating lipid trafficking and metabolism, there is increasing evidence that apoE-containing lipoproteins are also involved in dendritic remodeling and synaptogensis and maintenance of the synapto-dendritic complexity during aging. Interestingly, these functions have been shown to be apoE-isoform specific with apoE4 lacking the activities of apoE3 and apoE2. In addition to the association between apoE4 and an increased risk of AD, oxidative stress is believed to play a role in the pathogenesis of this disease. Indeed evidence of lipid peroxidation in cerebral spinal fluid (CSF) lipoproteins from AD patients has been observed. Oxidation of lipoproteins not only eliminates their supportive roles in neurite outgrowth and synaptogenesis, but actually transforms them into neurotoxic agents. The elucidation of the pathways and mechanisms by which apoE-isoform and oxidation affect lipoprotein function in the CNS remains a challenge for scientist in the field of neurodegenerative disease.

[The evaluation of susceptibility to oxidation of selected lipoproteins of pregnant women with type B diabetes mellitus in 2nd and 3rd trimester of pregnancy]. / Ocena podatnosci na proces oksydacji wybranych lipoprotein u ciezarnych chorych na cukrzyce klasy B w II i III trymestrze ciazy.

OBJECTIVES AND DESIGN: The aim of study was estimation of susceptibility on the process of oxidation of selected lipoproteins of pregnant women with IDDM in II, III trimester of pregnancy. MATERIALS AND METHODS: Study included 80 women. Patients were divided into four groups: pregnant with IDDM, pregnant healthy, nonpregnant with and without IDDM. We used spectrophotometric method for estimation of susceptibility on oxidation of HDL, LDL in the four groups of patients. RESULTS: In the group of diabetic pregnant we found increased serum concentrations of LDL. The comparison of examined groups showed statistically significant higher susceptibility on the oxidation of chosen lipoproteins in pregnant with IDDM. This group of patients characterized lower antioxidation activity than other groups. CONCLUSIONS: Diabetic pregnant characterized higher serum concentrations of LDL, and increase of peroxidation of lipids than other groups. This group showed lower total antioxidation activity. In the groups of diabetic women we obtained increased suspectibility of oxidation LDL and HDL.