NOTEWORTHY ARTICLES 2005

Neurobiology of Lipids 'Noteworthy' section alerts interested readers about the selected noteworthy original research (not review) articles and meeting reports (published in other journals) on the subject of the Neurobiology of Lipids scope.

The reference to each article may be accompanied by the referee name (a member of the Neurobiology of Lipids editorial board or a journal reader), the authors' key note comments, the date of the 'noteworthy' alert, NoL letter to editor, and links to related articles (if any).

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Noteworthy pages readership 1 January 2003 - 1 February 2005: 4742

Synaptic Activity Regulates Interstitial Fluid Amyloid-beta Levels In Vivo
Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM
Authors Institutions: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110; Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110; The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Neuron (22 December 2005) 48(6): 913-22
[PubMed] [Authors contact]
 

Article Abstract: "Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development."

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Decreased plasma cholesterol levels during aging in transgenic mouse models of Alzheimer's disease
Wirths O, Thelen K, Breyhan H, Luzon-Toro B, Hoffmann KH, Falkai P, Lutjohann D, Bayer TA
Department of Psychiatry, University of the Saarland, 66421 Homburg/Saar, Germany; Division of Neurobiology, University of the Saarland, 66421 Homburg/Saar, Germany
Exp Gerontol (20 November 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Article Abstract: "A large number of studies deals with the association of cholesterol and Abeta levels, however, the results are so far controversial. Whereas some studies report on increased cholesterol levels, other authors refer to an association of decreased peripheral cholesterol and the incidence of Alzheimer's disease. It is also questionable whether plasma cholesterol levels could be used as a predictive biomarker for the incidence of Alzheimer's disease. In the present report, we studied the relationship between these two parameters during aging in different transgenic mouse models of Alzheimer's disease, expressing both mutant human amyloid precursor protein and mutant human presenilin-1. Measurements of plasma cholesterol levels revealed a significant reduction in aged APP/PS1 and APP/PS1ki mice, whereas plasma levels in young and aged control mice remained almost unchanged. Furthermore, statistical analysis revealed a significant negative correlation between plasma cholesterol and brain Abeta42 levels during aging in the mice expressing both APP and PS1."

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Increased cholesterol in Abeta-positive nerve terminals from Alzheimer's disease cortex
Gylys KH, Fein JA, Yang F, Miller CA, Cole GM
UCLA School of Nursing, UCLA School of Medicine, Los Angeles, CA 90095, USA; Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA
Neurobiol Aging (2 December 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Article Abstract: "Synapse loss in Alzheimer's disease (AD) is poorly understood but evidence suggests it is a key pathological event. In order to precisely detect stable synaptic changes, we have developed methods for flow cytometry analysis of synaptosomes prepared from cryopreserved AD samples, and have previously shown that amyloid-beta (Abeta) accumulates in surviving presynaptic terminals in AD cortex. In the present experiments we have examined amyloid-containing terminals in more detail, first dual labeling synaptosomes from AD cortex for Abeta and a series of markers, and then using quadrant analysis to compare amyloid-positive and amyloid-negative terminals. Amyloid-positive synaptosomes were larger in size than amyloid-negatives (p<0.007), and significant increases were observed in mean fluorescence for the lipid raft markers cholesterol (27%; p<0.0005) and GM1 ganglioside (24%; p<0.005). SNAP-25 immunofluorescence was increased by 31% (p<0.0001) in amyloid-bearing terminals, consistent with a sprouting response to amyloid accumulation. These results suggest that Abeta accumulation in synaptic terminals may underly dysfunction prior to or independent of extracellular amyloid deposition."

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APOE-epsilon4 predisposes to cognitive dysfunction following uncomplicated carotid endarterectomy
Heyer EJ, Wilson DA, Sahlein DH, Mocco J, Williams SC, Sciacca R, Rampersad A, Komotar RJ, Zurica J, Benvenisty A, Quest DO, Todd G, Solomon RA, Connolly ES Jr
Department of Neurological Surgery, Columbia University, New York, NY 10032, USA
Neurology (13 December 2005) 65(11): 1759-63 ePub 6 October 2005
[PubMed] [Authors contact]
 

Article Abstract: "BACKGROUND: Between 9% and 23% of patients undergoing otherwise uncomplicated carotid endarterectomy (CEA) develop subtle cognitive decline 1 month postoperatively. The APOE-epsilon4 allele has been associated with worse outcome following stroke. OBJECTIVE: To investigate the ability of APOE-epsilon4 to predict post-CEA neurocognitive dysfunction. METHODS: Seventy-five patients with CEA undergoing elective CEA were prospectively recruited in this nested cohort study and demographic variables were recorded. Patients were evaluated before and 1 month after surgery with a standard battery of five neuropsychological tests. APOE genotyping was performed by restriction fragment length polymorphism analysis in all patients. Neuropsychological deficits were identified by comparing changes (before to 1 month post-operation) in individual performance on the test battery. Logistic regression was performed for APOE-epsilon4 and previously identified risk factors. RESULTS: Twelve of 75 (16%) CEA patients possessed the APOE-epsilon4 allele. Eight of 75 (11%) patients experienced neurocognitive dysfunction on postoperative day 30. One month post-CEA, APOE-epsilon4-positive patients were more likely to be cognitively injured (42%) than APOE-epsilon4-negative patients (5%) (p = 0.002). In multivariate analysis, the presence of the APOE-epsilon4 allele increased the risk of neurocognitive dysfunction at 1 month 62-fold (62.28, 3.15 to 1229, p = 0.007). Diabetes (51.42, 1.94 to 1363, p = 0.02), and obesity (24.43, 1.41 to 422.9, p = 0.03) also predisposed to injury. CONCLUSION: The APOE-epsilon4 allele is a robust independent predictor of neurocognitive decline 1 month following CEA."

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Reductions in cholesterol and synaptic markers in association cortex in mood disorders
Beasley CL, Honer WG, Bergmann K, Falkai P, Lutjohann D, Bayer TA
Center for Complex Disorders, Department of Psychiatry, University of British Columbia, Vancouver, Canada
Bipolar Disord (October 2005) 7(5): 449-55
[PubMed] [Authors contact]
 

Article Abstract: "OBJECTIVES: Cholesterol forms an integral part of cell membranes and is a major component of myelin. Furthermore, cholesterol also plays a vital role in the development, function and stability of synapses. While low serum cholesterol has previously been associated with mood disorders, cholesterol levels have yet to be quantified within the brain in these disorders. The aim of this study was to quantify sterol levels in the brains of patients with major psychiatric disorders and further to relate these levels to markers of myelin and synapses. METHODS: Samples of visual association cortex were obtained postmortem from subjects with bipolar disorder (BPD), major depressive disorder (MDD) and schizophrenia (SCZ) and from controls (all n = 15). Concentrations of brain cholesterol, its precursors lathosterol, desmosterol and lanosterol and its metabolite 24S-hydroxycholesterol were determined by gas-liquid chromatography. Immunoreactivity for myelin basic protein (MBP), synaptophysin and VAMP was quantified by enzyme-linked immunosorbent assay. RESULTS: Cholesterol levels were 13% lower in MDD (p = 0.018) and 10% lower in BPD (p = 0.052) compared with controls. Cholesterol precursor or metabolite concentrations did not differ between groups. Synaptophysin immunoreactivity was 20% lower in BPD (p = 0.025) and VAMP immunoreactivity 37% lower in MDD (p = 0.032) and 45% lower in BPD (p = 0.009). MBP immunoreactivity was not altered in any disorder. CONCLUSIONS: Our data suggest that lower brain cholesterol levels and a reduction in synapses may be features of mood disorders."

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Caveolin-1 expression and membrane cholesterol content modulate N-type calcium channel activity in NG108-15 cells
Toselli M, Biella G, Taglietti V, Cazzaniga E, Parenti M
Department of Cellular and Molecular Physiological and Pharmacological Sciences, and INFM (National Institute of Matter Physics), University of Pavia, Pavia, Italy
Biophys J (October 2005) 89(4): 2443-57 ePub 22 July 2005
[PubMed] [Authors contact]
 

Article Abstract: "Caveolins are the main structural proteins of glycolipid/cholesterol-rich plasmalemmal invaginations, termed caveolae. In addition, caveolin-1 isoform takes part in membrane remodelling as it binds and transports newly synthesized cholesterol from endoplasmic reticulum to the plasma membrane. Caveolin-1 is expressed in many cell types, including hippocampal neurons, where an abundant SNAP25-caveolin-1 complex is detected after induction of persistent synaptic potentiation. To ascertain whether caveolin-1 influences neuronal voltage-gated Ca2+ channel basal activity, we stably expressed caveolin-1 into transfected neuroblastoma x glioma NG108-15 hybrid cells [cav1(+) clone] that lack endogenous caveolins but express N-type Ca2+ channels upon cAMP-induced neuronal differentiation. Whole-cell patch-clamp recordings of cav1(+) cells demonstrated that N-type current density was reduced in size by approximately 70% without any significant change in the time course of activation and inactivation and voltage dependence. Moreover, the cav1(+) clone exhibited a significantly increased proportion of membrane cholesterol compared to wild-type NG108-15 cells. To gain insight into the mechanism underlying caveolin-1 lowering of N-current density, and more precisely to test whether this was indirectly caused by caveolin-1-induced enhancement of membrane cholesterol, we compared single N-type channel activities in cav1(+) clone and wild-type NG108-15 cells enriched with cholesterol after exposure to a methyl-beta-cyclodextrin-cholesterol complex. A lower Ca2+ channel activity was recorded from cell-attached patches of both cell types, thus supporting the view that the increased proportion of membrane cholesterol is ultimately responsible for the effect. This is due to a reduction in the probability of channel opening caused by a significant decrease of channel mean open time and by an increase of the frequency of null sweeps."

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Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain
Besshoh S, Bawa D, Teves L, Wallace MC, Gurd JW.
Centre for the Neurobiology of Stress, University of Toronto at Scarborough, Toronto, Canada
J Neurochem (April 2005) 93(1): 186-94
[PubMed] [Authors contact]
 

Article Abstract: "Ischemia results in increased phosphorylation of NMDA receptors. To investigate the possible role of lipid rafts in this increase, lipid rafts and post-synaptic densities (PSDs) were isolated by the extraction of rat brain synaptosomes with Triton X-100 followed by sucrose density gradient centrifugation. Lipid rafts accounted for the majority of PSD-95, whereas SAP102 was predominantly located in PSDs. Between 50 and 60% of NMDA receptors were associated with lipid rafts. Greater than 85-90% of Src and Fyn were present in lipid rafts, whereas Pyk2 was mainly associated with PSDs. Lipid rafts and PSDs were isolated from animals subjected to 15 min of global ischemia followed by 6 h of recovery. Ischemia did not affect the yield, density, flotillin-1 or cholesterol content of lipid rafts. Following ischemia, the phosphorylation of NR1 by protein kinase C and tyrosine phosphorylation of NR2A and NR2B was increased in both lipid rafts and PSDs, with a greater increase in tyrosine phosphorylation occurring in the raft fraction. Following ischemia, NR1, NR2A and NR2B levels were elevated in PSDs and reduced in lipid rafts. The findings are consistent with a model involving close interaction between lipid rafts and PSDs and a role for lipid rafts in ischemia-induced signaling pathways."

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Lipid raft localization of GABA A receptor and Na+, K+-ATPase in discrete microdomain clusters in rat cerebellar granule cells
Dalskov SM, Immerdal L, Niels-Christiansen LL, Hansen GH, Schousboe A, Danielsen EM
Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, 3 Blegdamsvej, DK-2200 Copenhagen N, Denmark
Neurochem Int (May 2005) 46(6): 489-99
[PubMed] [Authors contact]
 

Article Abstract: "The microdomain localization of the GABA(A) receptor in rat cerebellar granule cells was studied by subcellular fractionation and fluorescence- and immunogold electron microscopy. The receptor resided in lipid rafts, prepared at 37 degrees C by extraction with the nonionic detergent Brij 98, but the raft fraction, defined by the marker ganglioside GM(1) in the floating fractions following density gradient centrifugation, was heterogeneous in density and protein composition. Thus, another major raft-associated membrane protein, the Na(+), K(+)-ATPase, was found in discrete rafts of lower density, reflecting clustering of the two proteins in separate membrane microdomains. Both proteins were observed in patchy "hot spots" at the cell surface as well as in isolated lipid rafts. Their insolubility in Brij 98 was only marginally affected by methyl-beta-cyclodextrin. In contrast, both the GABA(A) receptor and Na(+), K(+)-ATPase were largely soluble in ice cold Triton X-100. This indicates that Brij 98 extraction defines an unusual type of cholesterol-independent lipid rafts that harbour membrane proteins also associated with underlying scaffolding/cytoskeletal proteins such as gephyrin (GABA(A) receptor) and ankyrin G (Na(+), K(+)-ATPase). By providing an ordered membrane microenvironment, lipid rafts may contribute to the clustering of the GABA(A) receptor and the Na(+), K(+)-ATPase at distinct functional locations on the cell surface."

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Proper axonal distribution of PrP(C) depends on cholesterol-sphingomyelin-enriched membrane domains and is developmentally regulated in hippocampal neurons
Galvan C, Camoletto PG, Dotti CG, Aguzzi A, Ledesma MD
Fondazione Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Turin), Italy
Mol Cell Neurosci (November 2005) 30(3): 304-15 ePub 1 Sep 2005
[PubMed] [Authors contact]
 

Article Abstract: "Defects in cellular localization and trafficking seem to facilitate the conversion of PrP(C) into the disease-associated form, PrP(Sc). Still, it is not clear to which membrane compartments PrP(C) localizes in hippocampal neurons a population most affected in the prion disease. We here show that in developing hippocampal neurons in culture PrP(C) is equally distributed to all neurites yet enriched in growth cones. By contrast, in fully mature neurons PrP(C) is restricted to axons. The axonal distribution in mature stages is paralleled by the increased partitioning of PrP(C) into detergent-resistant cholesterol-sphingolipid-rich domains (DRMs). Consistent with a cause-effect mechanism, disruption of DRMs by sphingolipid or cholesterol depletion leads to the non-polarized distribution and impaired endocytosis of PrP(C). These results indicate that DRMs are essential for proper trafficking and distribution of PrP(C) at late stages of neuronal differentiation and that its function, at least in hippocampus, is restricted to the axonal domain."

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Cholesterol-depleting compounds modulate K+-currents in Drosophila Kenyon cells
Gasque G, Labarca P, Darszon A
Departamento de Genetica del Desarrollo y Fisiologia Molecular, Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico
FEBS Lett (26 Sept 2005) 579(23): 5129-34
[PubMed] [Authors contact]
 

Article Abstract: "Sterol-enriched lipid rafts have been involved in Drosophila membrane signalling such as Hedgehog targeting and glutamate receptor ligand-affinity regulation. Here, we show that the voltage-dependent K(+) currents expressed by the intrinsic neurons of the Mushroom bodies are upward-modulated by compounds that remove sterols from the plasma membrane. Modulation seems to rely on a fast-exchanging sterol-pool, which more strongly affects the slowly inactivating current. Our results provide the first evidence that sterols influence the operation of voltage-gated ion channels in Drosophila neurons and strengthen the importance of lipid rafts in this biological model."

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Regulation of hippocampal cholesterol metabolism by apoE and environmental stimulation
Levi O, Lutjohann D, Devir A, von Bergmann K, Hartmann T, Michaelson DM.
J Neurochem (Nov 2005) 95(4): 987-97 ePub 29 September 2005
[PubMed] [Authors contact]
 

Article Abstract: "Alzheimer's disease is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and it is also affected by environmental factors such as early life education. We have recently shown, utilizing apoE-deficient and apoE transgenic mice, that synaptogenesis in the hippocampus following environmental stimulation is affected by apoE. In view of the pivotal role of cholesterol in synaptic plasticity, and of its suggested role in synaptogenesis, we presently examined the effects of apoE and environmental stimulation on brain cholesterol homeostasis. The hippocampal levels of cholesterol and its precursors and metabolites in control mice were not affected by exposure to environmental stimulation. In contrast, the hippocampal levels of cholesterol and its precursors lathosterol and desmosterol and metabolite 24S-hydroxycholesterol were lower in apoE-deficient mice that were maintained in a regular environmental than those of corresponding control mice, whereas they were markedly elevated following environmental stimulation. Histological and immunohistochemical experiments revealed that the combined stimulatory effects of apoE deficiency and environmental stimulation on cholesterol metabolism were associated with marked activation of hippocampal astrocytes and with the abnormal accumulation of cholesterol in neurons and astrocytes. These effects were rescued similarly in apoE3 and apoE4 transgenic mice. These findings suggest that apoE plays an important role in the translocation of cholesterol from astrocytes to neurons in vivo and in the regulation and homeostasis of this process."

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Immunohistochemical and microarray analyses of a mouse model for the Smith-Lemli-Opitz syndrome
Waage-Baudet H, Dunty Jr WC, Dehart DB, Hiller S, Sulik KK
Dev Neurosci (2005) 27(6): 378-96
[PubMed] [Authors contact]
 

Article Abstract: "The Smith-Lemli-Opitz syndrome is a mental retardation/malformation syndrome with behavioral components of autism. It is caused by a deficiency in 3beta-hydroxysteroid-Delta(7)-reductase (DHCR7), the enzyme required for the terminal enzymatic step of cholesterol biosynthesis. The availability of Smith-Lemli-Opitz syndrome mouse models has made it possible to investigate the genesis of the malformations associated with this syndrome. Dhcr7 gene modification (Dhcr7-/-) results in neonatal lethality and multiple organ system malformations. Pathology includes cleft palate, pulmonary hypoplasia, cyanosis, impaired cortical response to glutamate, and hypermorphic development of hindbrain serotonergic neurons. For the current study, hindbrain regions microdissected from gestational day 14 Dhcr7-/-, Dhcr7+/- and Dhcr7+/+ fetuses were processed for expression profiling analyses using Affymetrix oligonucleotide arrays and filtered using statistical significance (S-score) of change in gene expression. Of the 12,000 genes analyzed, 91 were upregulated and 98 were downregulated in the Dhcr7-/- hindbrains when compared to wild-type animals. Fewer affected genes, representing a reduced affect on these pathways, were identified in heterozygous animals. Hierarchical clustering identified altered expression of genes associated with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation and embryogenesis, transcription and translation, cellular transport, neurodegeneration, and neuronal cytoskeleton. Of particular interest, Dhcr7 gene modification elicited dynamic changes in genes involved in axonal guidance. In support of the microarray findings, immunohistochemical analyses of the netrin/deleted in colorectal cancer axon guidance pathway illustrated midline commissural deficiencies and hippocampal pathfinding errors in Dhcr7-/- mice. The results of these studies aid in providing insight into the genesis of human cholesterol-related birth defects and neurodevelopmental disorders and highlight specific areas for future investigation."

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Cholesterol-mediated neurite outgrowth is differently regulated between cortical and hippocampal neurons
Ko M, Zou K, Minagawa H, Yu W, Gong JS, Yanagisawa K, Michikawa M
Alzheimer's Disease Research, National Institute for Longevity Sciences, Obu, Aichi 474-8522
J Biol Chem (7 November 2005) ePub ahead of print  doi: 10.1074/jbc.M509164200
[PubMed] [Authors contact]
 

Article Abstract: "The acquisition of neuronal-type-specific morphogenesis is a central feature of neuronal differentiation and has important consequences for region-specific nervous system functions. Here, we report that the cell-type specific cholesterol profile determines the differential modulation of axon and dendrite outgrowths in hippocampal and cerebral cortical neurons in culture. The extent of axon and dendrite outgrowths is greater and the polarity formation occurs earlier in cortical neurons than in hippocampal neurons. The cholesterol concentrations in total homogenate and the lipid rafts from hippocampal neurons are significantly higher than those from cortical neurons. Cholesterol depletion by ss-cyclodextrin markedly enhanced the neurite outgrowth and accelerated the establishment of neuronal polarity in hippocampal neurons, which are similarly observed in nontreated cortical neurons, whereas the cholesterol loading had no effects. In contrast, both depletion and loading of cholesterol decreased the neurite outgrowths in cortical neurons. The stimulation of neurite outgrowth and polarity formation induced by cholesterol depletion was accompanied by an enhanced localization of Fyn, a Src kinase, in the lipid rafts of hippocampal neurons. A concomitant treatment with ss-cyclodextrin and a Src family kinase inhibitor, PP2, specifically blocked axon outgrowth, but not dendrite outgrowth, both of which were enhanced by ss-cyclodextrin, in hippocampal neurons, suggesting that axon outgrowth modulated by cholesterol is induced in a Fyn-dependent manner. These results suggest that cellular cholesterol modulates axon and dendrite outgrowths and neuronal polarization under cultured conditions, and that the difference in cholesterol profile between hippocampal and cortical neurons underlies the difference in neurite outgrowth between these two types of neuron."

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Dysfunction of the cholesterol biosynthetic pathway in Huntington's disease
Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, Strand A, Tarditi A, Woodman B, Racchi M, Mariotti C, Di Donato S, Corsini A, Bates G, Pruss R, Olson JM, Sipione S, Tartari M, Cattaneo E.
Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy
J Neurosci (26 October 2005) 25(43): 9932-9
[PubMed] [Authors contact]
 

Article Abstract: "The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an approximately 50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dose-dependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker."

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The apoE isoform binding properties of the VLDL receptor reveal marked differences from LRP and the LDL receptor
Ruiz J, Kouiavskaia D, Migliorini M, Robinson S, Saenko EL, Gorlatova N, Li D, Lawrence D, Hyman BT, Weisgraber KH, Strickland DK.
Department of Surgery, University of Maryland School of Medicine, Rockville, MD 21201, USA
J Lipid Res (Aug 2005) 46(8): 1721-31.
[PubMed] [Authors contact]
 

Article Abstract: "Apolipoprotein E (apoE) associates with lipoproteins and mediates their interaction with members of the LDL receptor family. ApoE exists as three common isoforms that have important distinct functional and biological properties. Two apoE isoforms, apoE3 and apoE4, are recognized by the LDL receptor, whereas apoE2 binds poorly to this receptor and is associated with type III hyperlipidemia. In addition, the apoE4 isoform is associated with the common late-onset familial and sporadic forms of Alzheimer's disease. Although the interaction of apoE with the LDL receptor is well characterized, the specificity of other members of this receptor family for apoE is poorly understood. In the current investigation, we have characterized the binding of apoE to the VLDL receptor and the LDL receptor-related protein (LRP). Our results indicate that like the LDL receptor, LRP prefers lipid-bound forms of apoE, but in contrast to the LDL receptor, both LRP and the VLDL receptor recognize all apoE isoforms. Interestingly, the VLDL receptor does not require the association of apoE with lipid for optimal recognition and avidly binds lipid-free apoE. It is likely that this receptor-dependent specificity for various apoE isoforms and for lipid-free versus lipid-bound forms of apoE is physiologically significant and is connected to distinct functions for these receptors."

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A role for caveolin-1 in post-injury reactive neuronal plasticity
Gaudreault SB, Blain JF, Gratton JP, Poirier J
Douglas Hospital Research Center, Neurological Sciences Department, McGill University, Montreal, Canada
J Neurochem (February 2005) 92(4): 831-9.
[PubMed] [Authors contact]
 

Article Abstract: "Remodeling and plasticity in the adult brain require cholesterol redistribution and synthesis for the formation of new membrane components. Caveolin-1 is a cholesterol-binding membrane protein involved in cellular cholesterol transport and homeostasis. Evidence presented here demonstrates an up-regulation of caveolin-1 in the hippocampus, which was temporally correlated with an increase in synaptophysin during the reinnervation phase in a mouse model of hippocampal deafferentation. Using an in vitro model of neuronal reactive plasticity, we examined the effect of virally mediated overexpression of caveolin-1 on injured differentiated PC12 cells undergoing terminal remodeling. Three days post lesion, caveolin-1-overexpressing cells revealed increases in synaptophysin and GAP-43, two markers of neurite sprouting and synaptogenesis. Morphologically, caveolin-1-overexpressing cells showed a decrease in primary neurite outgrowth and branching as well as an increase in neurite density. Caveolin-1-overexpressing cells also revealed the presence of terminal swelling and beading along processes, consistent with a possible alteration of microtubules stability. Moreover, a focal enrichment of caveolin-1 immunofluorescence was observed at the bases of axonal and dendritic terminals of mouse primary hippocampal neurons. Altogether, these results indicate that caveolin-1 plays an active role in the regulation of injury-induced synaptic and terminal remodeling in the adult CNS."

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Cholesterol homeostasis failure as a unifying cause of synaptic degeneration
Koudinov AR, Koudinova NV.
Neurobiology of Lipids, P.O. Box 1665, Rehovot 76100, Israel
J Neurol Sci (15 March 2005) 229-230: 233-40. Epub 16 December 2004
[PubMed] [Authors contact]
 

Article Abstract: "We previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior. Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Abeta) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence suggest that (i) cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimer's disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome, and (ii) explains the overlap of neurodegenerative hallmarks across the spectrum of neurodegenerative diseases. Provided is evidence-based explanation of why extremely rare (but scientifically popular) cases of AD associated with mutations in amyloid beta protein precursor (APP) and presenilin (PS) genes, are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Abeta generation. The reciprocal effect of Abeta on cholesterol synthesis, cellular uptake, efflux and esterification is summarized, as well as the potential implication of such biological function for the compensatory Abeta-assisted restoration of the synaptic long-term potentiation (LTP) and resulting inability of tackling amyloid to cure AD."

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Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain
Besshoh S, Bawa D, Teves L, Wallace MC, Gurd JW
Centre for the Neurobiology of Stress, University of Toronto at Scarborough, Toronto, Canada
J Neurochem (April 2005) 93(1) 186-94
[PubMed] [Authors contact]
 

Article Abstract: "Ischemia results in increased phosphorylation of NMDA receptors. To investigate the possible role of lipid rafts in this increase, lipid rafts and post-synaptic densities (PSDs) were isolated by the extraction of rat brain synaptosomes with Triton X-100 followed by sucrose density gradient centrifugation. Lipid rafts accounted for the majority of PSD-95, whereas SAP102 was predominantly located in PSDs. Between 50 and 60% of NMDA receptors were associated with lipid rafts. Greater than 85-90% of Src and Fyn were present in lipid rafts, whereas Pyk2 was mainly associated with PSDs. Lipid rafts and PSDs were isolated from animals subjected to 15 min of global ischemia followed by 6 h of recovery. Ischemia did not affect the yield, density, flotillin-1 or cholesterol content of lipid rafts. Following ischemia, the phosphorylation of NR1 by protein kinase C and tyrosine phosphorylation of NR2A and NR2B was increased in both lipid rafts and PSDs, with a greater increase in tyrosine phosphorylation occurring in the raft fraction. Following ischemia, NR1, NR2A and NR2B levels were elevated in PSDs and reduced in lipid rafts. The findings are consistent with a model involving close interaction between lipid rafts and PSDs and a role for lipid rafts in ischemia-induced signaling pathways."

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Catabolism of native and oxidized low density lipoproteins (LDL): in vivo insights from small animal positron emission tomography studies
Pietzsch J, Bergmann R, Wuest F, Pawelke B, Hultsch C, van den Hoff J.
Positron Emission Tomography Center, Institute of Bioinorganic and Radiopharmaceutical Chemistry, Research Center Rossendorf, Dresden, Germany
Amino Acids (15 July 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Article Abstract: "The human organism is exposed to numerous processes that generate reactive oxygen species (ROS). ROS may directly or indirectly cause oxidative modification and damage of proteins. Protein oxidation is regarded as a crucial event in the pathogenesis of various diseases ranging from rheumatoid arthritis to Alzheimer's disease and atherosclerosis. As a representative example, oxidation of low density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Data concerning the role of circulating oxidized LDL (oxLDL) in the development and outcome of diseases are scarce. One reason for this is the shortage of methods for direct assessment of the metabolic fate of circulating oxLDL in vivo. We present an improved methodology based on the radiolabelling of apoB-100 of native LDL (nLDL) and oxLDL, respectively, with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). Radiolabelling of both nLDL and oxLDL using [(18)F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively, in vitro. The method was further evaluated with respect to the radiopharmacological properties of both [(18)F]fluorobenzoylated nLDL and oxLDL by biodistribution studies in male Wistar rats. The metabolic fate of [(18)F]fluorobenzoylated nLDL and oxLDL in rats in vivo was further delineated by dynamic positron emission tomography (PET) using a dedicated small animal tomograph (spatial resolution of 2 mm). From this study we conclude that the use of [(18)F]FB-labelled LDL particles is an attractive alternative to, e.g., LDL iodination methods, and is of value to characterize and to discriminate the kinetics and the metabolic fate of nLDL and oxLDL in small animals in vivo."

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Association Study of the A2M and LRP1 Genes with Alzheimer Disease in the Han Chinese
Bian L, Yang JD, Guo TW, Duan Y, Qin W, Sun Y, Feng GY, He L
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; Bio-X Center, Shanghai Jiao Tong University
J Neurol (17 August 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Article Abstract: "BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) and alpha-2-macroglobulin (A2M) are two plausible candidate genes for Alzheimer disease (AD) based on their important biological function and positional information. To date, numerous studies have investigated their possible association with AD but the results are controversial. METHODS: To investigate the potential genetic contribution of the two genes in the Han Chinese population, we performed a case-control association study using 10 polymorphisms (4 in LRP1 and 6 in A2M) that span approximately the whole corresponding gene. RESULTS: Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects. For the LRP1 gene, however, we found an overrepresentation of the CTCG haplotype in the control group (p = .002). The difference was still of statistical significance in the apolipoprotein E (APOE) epsilon 4 negative subjects (p(CTCG) = .003). Multiple logistic regression analysis did not show any evidence of synergism between A2M, LRP1, and APOE. CONCLUSIONS: Our results indicate that the CTCG haplotype of LRP1 may reduce the risk of late-onset AD, but A2M is not associated with this disease in the Han Chinese population."

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Lack of association between the CYP46 gene polymorphism and Italian late-onset sporadic Alzheimer's disease
Tedde A, Rotondi M, Cellini E, Bagnoli S, Muratore L, Nacmias B, Sorbi S
Department of Neurological and Psychiatric Sciences, University of Florence, Viale Pieraccini, 6 50139 Florence, Italy
Neurobiol Aging (28 July 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Article Abstract: "Recent studies have provided evidence toward the possible involvement of brain cholesterol homeostasis in late-onset Alzheimer's disease (LOAD). We analyzed an intronic T-->C substitution (rs 754203) of the cholesterol 24S-hydroxylase (CYP46) gene, encoding an enzyme acting on brain cholesterol turnover, which has been recently associated with an increased risk of AD, dependent or not on Apolipoprotein E (ApoE) genotype. No significant association was found for the CYP46 polymorphism in LOAD compared to the controls, even after stratification for the presence/absence of the ApoE*4 allele. Our data do not support a role of the CYP46 polymorphism as a possible susceptibility factor for developing AD."

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Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE epsilon4 allele
Rodriguez E, Mateo I, Infante J, Llorca J, Berciano J, Combarros O
Neurology Service, University Hospital "Marques de Valdecilla", University of Cantabria, 39008-Santander, Spain
J Neurol (17 August 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Article Abstract: "Cholesterol regulates the production of amyloid beta (Abeta),which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C-629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 carriers, homozygous for the CETP (-629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01-5.37), than homozygous and heterozygous carriers of the CETP (-629) C allele (odds ratio 7.12, 95% CI 4.51-11.24, P for APOE epsilon4/CETP (-629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE epsilon4 allele, possibly through modulation of brain cholesterol metabolism."

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Cholesterol-dependent lipid assemblies regulate the activity of the ecto-nucleotidase CD39
Papanikolaou A, Papafotika A, Murphy C, Papamarcaki T, Tsolas O, Drab M, Kurzchalia TV, Kasper M, Christoforidis S
Laboratory of Biological Chemistry, Medical School, University of Ioannina, 45110 Ioannina, Greece
Biol Chem (15 Julyr 2005) 280(28): 26406-24
[PubMed] [Authors contact]
 

Article Abstract: "CD39 (ecto-nucleoside triphosphate diphosphohydrolase-1; E-NTPDase1) is a plasma membrane ecto-enzyme that regulates purinergic receptor signaling by controlling the levels of extracellular nucleotides. In blood vessels this enzyme exhibits a thromboregulatory role through the control of platelet aggregation. CD39 is localized in caveolae, which are plasma membrane invaginations with distinct lipid composition, similar to dynamic lipid microdomains, called rafts. Cholesterol is enriched together with sphingolipids in both rafts and caveolae, as well as in other specialized domains of the membrane, and plays a key role in their function. Here, we examine the potential role of cholesterol-enriched domains in CD39 function. Using polarized Madin-Darby canine kidney (MDCK) cells and caveolin-1 gene-disrupted mice, we show that caveolae are not essential either for the enzymatic activity of CD39 or for its targeting to plasma membrane. On the other hand, flotation experiments using detergent-free or detergent-based approaches indicate that CD39 associates, at least in part, with distinct lipid assemblies. In the apical membrane of MDCK cells, which lacks caveolae, CD39 is localized in microvilli, which are also cholesterol and raft-dependent membrane domains. Interfering with cholesterol levels using drugs that either deplete or sequester membrane cholesterol results in a strong inhibition of the enzymatic and anti-platelet activity of CD39. The effects of cholesterol depletion are completely reversed by replenishment of membranes with pure cholesterol, but not by cholestenone. These data suggest a functional link between the localization of CD39 in cholesterol-rich domains of the membrane and its role in thromboregulation."

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Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro
M Sinagra, D Verrier, D Frankova, KM Korwek, J Blahos, EJ Weeber, OJ Manzoni, and P Chavis
J Neurosci (29 June 2005) 25(26): 6127
[Abstract@PubMed] [Authors contact]

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Vitamin E in neurodegenerative disorders: Alzheimer's disease
Kontush K, Schekatolina S
Ann N Y Acad Sci (December 2004) 1031(1): 87-94
[PubMed] [Authors contact]

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Caveolin-1 expression and membrane cholesterol content modulate N-type calcium channel activity in NG108-15 cells
Toselli M, Biella G, Taglietti V, Cazzaniga E, Parenti M
Department of Cellular and Molecular Physiological and Pharmacological Sciences, and INFM (National Institute of Matter Physics), University of Pavia, Pavia, Italy
Biophys J (Oct 2005) 89(4): 2443-57 ePub 22 July 2005
[PubMed] [Authors contact]
 

Article Abstract: "Caveolins are the main structural proteins of glycolipid/cholesterol-rich plasmalemmal invaginations, termed caveolae. In addition, caveolin-1 isoform takes part in membrane remodelling as it binds and transports newly synthesized cholesterol from endoplasmic reticulum to the plasma membrane. Caveolin-1 is expressed in many cell types, including hippocampal neurons, where an abundant SNAP25-caveolin-1 complex is detected after induction of persistent synaptic potentiation. To ascertain whether caveolin-1 influences neuronal voltage-gated Ca2+ channel basal activity, we stably expressed caveolin-1 into transfected neuroblastoma x glioma NG108-15 hybrid cells [cav1(+) clone] that lack endogenous caveolins but express N-type Ca2+ channels upon cAMP-induced neuronal differentiation. Whole-cell patch-clamp recordings of cav1(+) cells demonstrated that N-type current density was reduced in size by approximately 70% without any significant change in the time course of activation and inactivation and voltage dependence. Moreover, the cav1(+) clone exhibited a significantly increased proportion of membrane cholesterol compared to wild-type NG108-15 cells. To gain insight into the mechanism underlying caveolin-1 lowering of N-current density, and more precisely to test whether this was indirectly caused by caveolin-1-induced enhancement of membrane cholesterol, we compared single N-type channel activities in cav1(+) clone and wild-type NG108-15 cells enriched with cholesterol after exposure to a methyl-beta-cyclodextrin-cholesterol complex. A lower Ca2+ channel activity was recorded from cell-attached patches of both cell types, thus supporting the view that the increased proportion of membrane cholesterol is ultimately responsible for the effect. This is due to a reduction in the probability of channel opening caused by a significant decrease of channel mean open time and by an increase of the frequency of null sweeps."

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Association between acyl-coenzyme A: cholesterol acyltransferase (ACAT) gene and risk for Alzheimer's disease in Chinese
Zhao FG, Wang YH, Yang JF, Ma QL, Tang Z, Dong XM, Chan P
Neuroscience Lett (22 July 2005) ePub ahead of Print
[Abstract@PubMed] [Authors contact]

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Cholesterol-dependent modulation of type 1 cannabinoid receptors in nerve cells
Bari M, Paradisi A, Pasquariello N, Maccarrone M
Department of Biomedical Sciences, University of Teramo, Teramo, Italy
J Neurosci Res (15 July 2005) 81(2): 275-83
[PubMed] [Authors contact]
 

Article Abstract: "Type 1 cannabinoid receptors (CB1R) are G-protein-coupled receptors that mediate several actions of the endocannabinoid anandamide (N-arachidonoylethanolamine; AEA) in the central nervous system. Here we show that cholesterol enrichment of rat C6 glioma cell membranes reduces by approximately twofold the binding efficiency (i.e., the ratio between maximum binding and dissociation constant) of CB1R and that activation of CB1R by AEA leads to approximately twofold lower [(35)S]GTPgammaS binding in cholesterol-treated cells than in controls. In addition, we show that CB1R-dependent signaling via adenylate cyclase and p42/p44 mitogen-activated protein kinase is almost halved by cholesterol enrichment. Unlike CB1R, the other AEA-binding receptor TRPV1, the AEA synthetase NAPE-PLD, and the AEA hydrolase FAAH are not modulated by cholesterol, whereas the catalytic efficiency (i.e., the ratio between maximal velocity and Michaelis-Menten constant) of the AEA membrane transporter AMT is almost doubled compared with control cells. These data demonstrate that, among the proteins of the "endocannabinoid system," only CB1R and AMT critically depend on membrane cholesterol content. This observation may have important implications for the role of CB1R in protecting nerve cells against (endo)cannabinoid-induced apoptosis."

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Alpha-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease
Halliday GM, Ophof A, Broe M, Jensen PH, Kettle E, Fedorow H, Cartwright MI, Griffiths FM, Shepherd CE, Double KL
Prince of Wales Medical Research Institute and the University of New South Wales, Sydney, Australia
Brain (Oct 2005) 128(Pt 11): 2654-64 ePub 6 July 2005
[PubMed] [Authors contact]
 

Article Abstract: "The distribution and tempo of neuronal loss in Parkinson's disease correlates poorly with the characteristic and more widely spread intracellular changes associated with the disease process (Lewy bodies and Lewy neurites). To determine early intracellular changes in regions where cell loss is most marked (dopaminergic A9 substantia nigra) versus regions with Lewy bodies but where cell loss is limited, we assessed 13 patients with definite Parkinson's disease at various disease stages in comparison with controls. Using immunohistochemistry for alpha-synuclein, we confirmed the concentration of this protein in the soma of normal A9 neurons and in Lewy body pathology in brainstem catecholamine neurons in Parkinson's disease. Analysis of the degree of cell loss in brainstem catecholamine cell groups revealed that only the A9 substantia nigra had consistent significant cell loss early in the disease course with greater A9 cell loss correlating with increasing disease duration. To assess the earliest intracellular changes differentiating neurons more likely to degenerate, pigmented A9 and A10 neurons with and without obvious pathology were targeted, cell size and pigment density measured, and intracellular changes in alpha-synuclein location and lipid components analysed at both the light and electron microscope levels. There were no changes observed in healthy A10 neurons in Parkinson's disease compared with controls. Pigmented A9 neurons in later stages of degeneration with obvious Lewy body formation had a significant reduction in intracellular pigment, as previously described. In contrast, A9 neurons of normal morphological appearance and no characteristic pathology in Parkinson's disease exhibited significantly increased pigment density associated with a concentration of alpha-synuclein to the lipid component of the pigment and a loss of associated cholesterol. These changes in vulnerable but apparently healthy A9 neurons occurred without any change in cell size or in the amount of intracellular pigment compared with controls. The increase in pigment density is consistent with previously reported increases associated with oxidation and iron loading, reactions known to precipitate alpha-synuclein. The selectivity of the changes observed in A9 nigral neurons suggests that these early intracellular changes predispose these neurons to more rapid cell loss in Parkinson's disease. The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. Overall, these changes may trigger a cascade of events leading to larger intracellular aggregates of alpha-synuclein and the dispersement of protective pigment to precipitate cell death in Parkinson's disease."

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No Genetic Association between ATP Binding Cassette Proteins and Japanese Sporadic Alzheimer's Disease
Ohkubo T, Shibata N, Ohnuma T, Higashi S, Usui C, Ueki A, Nagao M, Arai H
Dement Geriatr Cogn Disord (23 June 2005) 20(2-3): 95-98
[Abstract@PubMed] [Authors contact]

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Neuronal Nitric Oxide Synthase Mediates Statin-Induced Restoration of Vasa Nervorum and Reversal of Diabetic Neuropathy
Masaaki Ii, Hiromi Nishimura, Kengo F Kusano, Gangjian Qin, Young-Sup Yoon, Andrea Wecker, Takayuki Asahara, and Douglas W Losordo
Circulation (27 June 2005)
[Abstract@PubMed] [Authors contact]

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Dietary fatty acids and the risk of Parkinson disease: the Rotterdam study
LM de Lau, M Bornebroek, JC Witteman, A Hofman, PJ Koudstaal, and MM Breteler
Neurology (28 June 2005) 64(12): 2040
[Abstract@PubMed] [Authors contact]

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24S-hydroxycholesterol induces inflammatory gene expression in primary human neural cells
Alexandrov P, Cui JG, Zhao Y, Lukiw WJ
Russian Academy of Medical Sciences, Moscow 113152, Russia
Neuroreport (21 June 2005) 16(9): 909-13
[PubMed] [Authors contact]
 

Article Abstract: "24S-hydroxycholesterol, the primary oxidation product of cholesterol in the brain, plays a key role in cholesterol elimination and homeostasis. While the concentration of this neurotoxic oxysterol decreases with age, 24S-hydroxycholesterol is elevated in Alzheimer's disease. In this study, we examined the effects of 24S-hydroxycholesterol on gene expression in human neural cells, a primary coculture of neurons and glia useful for studying pathogenic mechanisms in Alzheimer's disease. DNA array and Western analysis revealed elevations in the expression of a pro-inflammatory gene family that included beta-amyloid precursor protein, cyclooxygenase-2, cytosolic phospholipase A2 and heat shock protein 70, an effect that was partially suppressed by simvastatin. These data indicate that cholesterol oxides induce atypical gene expression in neural cells that may contribute to the etiology or pathogenesis of inflammatory brain disease."

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Reduced CSF PLTP activity in Alzheimer's disease and other neurologic diseases; PLTP induces ApoE secretion in primary human astrocytes in vitro
Vuletic S, Peskind ER, Marcovina SM, Quinn JF, Cheung MC, Kennedy H, Kaye JA, Jin LW, Albers JJ
Department of Medicine, Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington, USA
J Neurosci Res (28 March 2005) 80(3): 406-413
[PubMed] [Authors contact]

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High-cholesterol diets impair short-term retention of memory in alloxan-induced diabetic mice, but not acquisition of memory nor retention of memory in prediabetic mice
Xie W, Du L
Life Sci (17 June 2005) 77(5): 481-495
[PubMed] [Authors contact]

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Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron
Goritz C, Mauch DH, Pfrieger FW
Mol Cell Neurosci (11 April 2005) 29(2): 190-201
[Abstract@PubMed] [Related articles: 1 | 2 | 3 | 4][Authors contact]

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The protective action of alpha-tocopherol on the white matter lipids during moderate hypoxia in rats
Kapelusiak-Pielok M, Adamczewska-Goncarzewicz Z, Dorszewska J, Grochowalska A
Folia Neuropathol (2005) 43(2): 103-108
[PubMed] [Authors contact]

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Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J, Ziolwolski C
Arch Neurol (May 2005) 62(5): 753-757
[Abstract@PubMed] [Authors contact]

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Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease
Li H, Repa JJ, Valasek MA, Beltroy EP, Turley SD, German DC, Dietschy JM
J Neuropathol Exp Neurol (April 2005) 64(4): 323-333
[Abstract@PubMed] [Authors contact]

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Synaptic proteins and SNARE complexes are localized in lipid rafts from rat brain synaptosomes
Gil C, Soler-Jover A, Blasi J, Aguilera J
Biochem Biophys Res Commun (1 April 2005) 329(1): 117-124
[Abstract@PubMed] [Authors contact]

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Multiple pathways of apolipoprotein E signaling in primary neurons
Hoe HS, Harris DC, Rebeck GW
J Neurochem (April 2005) 93(1): 145-155
[Abstract@PubMed] [Authors contact]

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Delayed olfactory nerve regeneration in ApoE-deficient mice
Nathan BP, Nisar R, Short J, Randall S, Grissom E, Griffin G, Switzer PV, Struble RG
J Neurochem (11 April 2005) 1041(1): 87-94
[PubMed] [Authors contact]

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Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J
J Neurochem (18 Oct 2002) 277(42): 39944-52
[PubMed] [Authors contact]

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The low-density lipoprotein receptor regulates the level of CNS human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice
Fryer JD, Demattos RB, McCormick LM, O'dell MA, Spinner ML, Bales KR, Paul SM, Sullivan PM, Parsadanian M, Bu G, Holtzman DM
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
J Biol Chem (11 May 2005) 280(27), 25754-9 [ePub ahead of print]
[PubMed] [Authors contact]
 

Abstract: "Apolipoprotein E (apoE), a chaperone for the amyloid beta (Abeta) peptide, regulates the deposition and structure of Abeta that deposits in the brain in Alzheimer disease (AD). The primary apoE receptor that regulates levels of apoE in the brain is unknown. We report that the low density lipoprotein receptor (LDLR) regulates the cellular uptake and central nervous system levels of astrocyte-derived apoE. Cells lacking LDLR were unable to appreciably endocytose astrocyte-secreted apoE-containing lipoprotein particles. Moreover, cells overexpressing LDLR showed a dramatic increase in apoE endocytosis and degradation. We also found that LDLR knock-out (Ldlr-/-) mice had a significant, approximately 50% increase in the level of apoE in the cerebrospinal fluid and extracellular pools of the brain. However, when the PDAPP mouse model of AD was bred onto an Ldlr-/- background, we did not observe a significant change in brain Abeta levels either before or after the onset of Abeta deposition. Interestingly, human APOE3 or APOE4 (but not APOE2) knock-in mice bred on an Ldlr-/- background had a 210% and 380% increase, respectively, in the level of apoE in cerebrospinal fluid. These results demonstrate that central nervous system levels of both human and murine apoE are directly regulated by LDLR. Although the increase in murine apoE caused by LDLR deficiency was not sufficient to affect Abeta levels or deposition by 10 months of age in PDAPP mice, it remains a possibility that the increase in human apoE3 and apoE4 levels caused by LDLR deficiency will affect this process and could hold promise for therapeutic targets in AD."

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The Effect of Simvastatin Treatment on the Amyloid Precursor Protein and Brain Cholesterol Metabolism in Patients with Alzheimer's Disease
Hoglund K, Thelen KM, Syversen S, Sjogren M, von Bergmann K, Wallin A, Vanmechelen E, Vanderstichele H, Lutjohann D, Blennow K
Dement Geriatr Cogn Disord (21 March 2005) 19(5-6): 256-265
[PubMed] [Authors contact]

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Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease
Li H, Repa JJ, Valasek MA, Beltroy EP, Turley SD, German DC, Dietschy JM
J Neuropathol Exp Neurol (April 2005) 64(4): 323-333
[PubMed] [Authors contact]

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The Niemann-Pick type C disease and intracellular cholesterol trafficking
Chang TY, Reid PC, Sugii S, Ohgami N, Cruz JC, Chang CC
J Biol Chem (14 April 2005) [ePub ahead of print]
[PubMed] [Authors contact]

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Six novel NPC1 mutations in Chinese patients with Niemann-Pick disease type C
Yang CC, Su YN, Chiou PC, Fietz MJ, Yu CL, Hwu WL, Lee MJ
J Neurol Neurosurg Psychiatry (April 2005) 76(4): 592-595
[PubMed] [Authors contact]

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Structural basis for lipid modulation of nicotinic acetylcholine receptor function
Barrantes FJ
Brain Res Brain Res Rev (Dec 2004) 47(1-3): 71-95
[PubMed] [Authors contact]

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Changes in the neuromuscular synapse induced by an antibody against gangliosides
Santafe MM, Sabate MM, Garcia N, Ortiz N, Lanuza MA, Tomas J
Ann Neurol (March 2005) 57(3): 396-407
[PubMed] [Authors contact]

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Synaptic proteins and SNARE complexes are localized in lipid rafts from rat brain synaptosomes
Gil C, Soler-Jover A, Blasi J, Aguilera J
Biochem Biophys Res Commun (1 April 2005) 329(1): 117-124
[PubMed] [Authors contact]

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Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution
Abulrob A, Tauskela JS, Mealing G, Brunette E, Faid K, Stanimirovic D
J Biol Chem (March 2005) 92(6): 1477-86
[PubMed] [Authors contact]

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The regulation of beta-secretase by cholesterol and statins in Alzheimer's disease
Sidera C, Parsons R, Austen B
J Neurol Sci (15 March 2005) 229-230: 269-273
[PubMed] [Authors contact]

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Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function
Yu W, Gong JS, Ko M, Garver WS, Yanagisawa K, Michikawa M
J Biol Chem (25 March 2005) 280(12): 11731-11739
[PubMed] [Authors contact]

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Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice--a model of familial amyotrophic lateral sclerosis
Perluigi M, Fai Poon H, Hensley K, Pierce WM, Klein JB, Calabrese V, De Marco C, Butterfield DA
Free Radic Biol Med (1 April 2005) 38(7): 960-968
[PubMed] [Authors contact]

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Cholinesterase Inhibitor Affects the Amyloid Precursor Protein Isoforms in Patients with Alzheimer's Disease
Liu HC, Chi CW, Ko SY, Wang HC, Hong CJ, Lin KN, Wang PN, Liu TY
Dement Geriatr Cogn Disord (22 March 2005) 19(5-6): 345-348
[PubMed] [Authors contact]

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The apoE receptor apoER2 is involved in the maintenance of efficient synaptic plasticity
Petit-Turcotte C, Aumont N, Beffert U, Dea D, Herz J, Poirier J
Neurobiol Aging (Feb 2005) 26(2): 195-206
[PubMed] [Authors contact]

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Dolichol is the major lipid component of human substantia nigra neuromelanin
Fedorow H, Pickford R, Hook JM, Double KL, Halliday GM, Gerlach M, Riederer P, Garner B.
J Neurochem (Feb 2005) 92(4): 990-995
[PubMed] [Authors contact]

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Genetic-morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathy
Christoforidis M, Schober R, Krohn K
Neuropathol Appl Neurobiol (Feb 2005) 31(1): 11-19
[PubMed] [Authors contact]

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Statins cause intracellular accumulation of APP, beta-secretase cleaved fragments, and Abeta via an isoprenoid-dependent mechanism
Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R
J Biol Chem (17 February 2005) ePub ahead of print
[PubMed] [Authors contact]
 

Keynote by Sarah Cole: "In agreement with previous reports, we demonstrate that low cellular cholesterol levels favor a reduction in Amyloid beta (Abeta, Ab) secretion. Conversely, we made the novel observation that low cellular isoprenoids promote intracellular Ab accumulation. Interestingly, cholesterol and isoprenoids have completely independent effects on Ab secretion and accumulation, respectively. We have identified two distinct pools of Ab, an intracellular, isoprenoid-dependent pool, and an extracellular, cholesterol-dependent pool. We hypothesize that the protective effects of statins in AD may be due, in part at least, to lower cerebral cholesterol levels. While it is unlikely that statin concentrations in the brain are high enough to inhibit the isoprenoid pathway, several reports have recently described intraneuronal Abeta accumulation in AD. However, the role of Ab accumulation in AD remains an open question. We observed that low cellular isoprenoids increase intracellular Ab levels. Thus, we speculate that the intraneuronal Ab accumulation observed in AD may result from isoprenoid deficiency in the neuron. If intraneuronal Ab accumulation is toxic, then our work implies that increasing isoprenoid synthesis or function in neurons may prove to be an efficacious therapeutic strategy for AD treatment."

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A role for caveolin-1 in post-injury reactive neuronal plasticity
Gaudreault SB, Blain JF, Gratton JP, Poirier J
J Neurochem (Feb 2005) 92(4): 831-9 doi:10.1111/j.1471-4159.2004.02917.x
[PubMed] [Authors contact]

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Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions
Yamashita T, Wu YP, Sandhoff R, Werth N, Mizukami H, Ellis JM, Dupree JL, Geyer R, Sandhoff K, Proia RL
Proc Natl Acad Sci USA (14 February 2005) ePub ahead of print
[PubMed] [Authors contact]

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BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation
Suzuki S, Numakawa T, Shimazu K, Koshimizu H, Hara T, Hatanaka H, Mei L, Lu B, Kojima M
J Cell Biol (20 December 2004) 167(6): 1205-15
[PubMed] [Authors contact]
 

Keynote by Masami Kojima: "Brain-derived neurotrophic factor (BDNF) exerts many biological effects in nervous system but the underlying signaling mechanisms remain unknown. Here we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from non-raft regions of neuronal plasma membranes. Translocation of TrkB-FL into rafts is required for BDNF regulation of synaptic plasticity, dendritic extention, but not cell survival."

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Association of active gamma-secretase complex with lipid rafts
Urano Y, Hayashi I, Isoo N, Reid PC, Shibasaki Y, Noguchi N, Tomita T, Iwatsubo T, Hamakubo T, Kodama T
J Lipid Res (16 February 2005) ePub ahead of print
[PubMed] [Authors contact]

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The immunodetection of lipoprotein-bound amyloid-beta is attenuated because of the presence of lipids
James AP, Mamo JC
School of Public Health and the Western Australian Biomedical Research Institute, Curtin University of Technology, Kent Street Bentley 6102, Western Australia
Ann Clin Biochem (January 2005) 42(1): 70-72
[Abstract@PubMed] [Authors contact]

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Ginkgo biloba extract (Egb 761) inhibits beta-amyloid production by lowering free cholesterol levels
Yao ZX, Han Z, Drieu K, Papadopoulos V
J NUTRITIONAL BIOCHEM (Dec 2004) 15(2): 749-756
[PubMed] [Authors contact]
 

Keynote by Dr. ZX Yao: "The molecular mechanisms by which the standardized Ginkgo biloba extract EGb 761 can improve cognitive function in patients afflicted with Alzheimer's disease remain undefined. It has been suggested that free cholesterol may be involved in the production of beta-amyloid precursor protein (bPP) and beta-amyloid peptide (Ab), key events in the development of Alzheimer's disease. The data presented in this manuscript show that EGb 761 treatment decreased the capacity of low density lipoproteins (LDL) to carry cholesterol, thus lowering the levels of circulating free cholesterol. The later event resulted in inhibition of the production of brain beta-amyloid precursor protein and beta-amyloid peptide in aging Brown Norway rats, offering a better understanding of the mechanisms underlying the beneficial effects of EGb 761 in Alzheimer's disease therapy."

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Cholesterol, transferrin saturation, and the development of dementia and Alzheimer's disease: results from an 18-year population-based cohort
Mainous AG 3rd, Eschenbach SL, Wells BJ, Everett CJ, Gill JM
Fam Med (January 2005) 37(1): 36-42
[PubMed] [Authors contact]

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Genetic association of low density lipoprotein receptor and Alzheimer's disease
Gopalraj RK, Zhu H, Kelly JF, Mendiondo M, Pulliam JF, Bennett DA, Estus S
Neurobiol Aging (Jan 2005) 26(1): 1-7 doi:10.1016/j.neurobiolaging.2004.09.001
[PubMed] [Authors contact]

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3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses
Cordle A, Landreth G
J Neurosci (12 January 2005) 25(2): 299-307
[PubMed] [Earlier NoL Article] [Authors contact]
 

Keynote by Andrew Cordle: "Statins have historically been administered to combat hypercholesterolemia however; recently they have been shown to also have potent anti-inflammatory actions. In the case of Alzheimer’s disease we feel these pleiotropic effects are responsible for the protection patients on these medications enjoy. Our studies have demonstrated that the anti-inflammatory actions of these compounds stem from their ability to inhibit the HMG-CoA reductase enzyme, but not from their ability to reduce cholesterol levels. This paradox can be explained by the role isoprenoids, intermediates in cholesterol biosynthesis, play in the modification of small G-proteins. Small G-proteins require the C-terminal addition of an isoprenyl group to allow membrane localization. Following statin administration and inhibition of HMG CoA reductase, intracellular levels of isoprenoids diminish and G-protein modification decreases. This acts to functionally inhibit G-protein function and ultimately blunts cellular pro-inflammatory reactions. This study expands our understanding of how statins modulate cellular processes and provides new targets for anti-inflammatory therapeutics." Original Abstract: "Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar beta-amyloid (Abeta) in the brain, a fulminant microglial-mediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the Abeta-stimulated expression of interleukin-1beta and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal Abeta production and microglia-directed inflammation."

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Modulation of Statin-Activated Shedding of Alzheimer APP Ectodomain by ROCK
Pedrini S, Carter TL, Prendergast G, Petanceska S, Ehrlich ME, Gandy S
PLoS Med (11 Jan 2005) 2(1): e18 doi: 10.1371/journal.pmed.0020018
[PubMed] [FullText] [Communication arizing] [AlzForum News] [Authors contact]

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Structural basis for lipid modulation of nicotinic acetylcholine receptor function
Barrantes FJ
Brain Res Brain Res Rev (December 2004) 47(1-3): 71-95
[Abstract@PubMed] [Authors contact]

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Obesity-related leptin regulates Alzheimer's Abeta
Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N
FASEB Journal (December 2004) 18(15): 1870-8.
[Abstract@PubMed] [Authors contact]

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Overexpression of genes in the CA1 hippocampus region of adult rat following episodes of global ischemia
Yakubov E, Gottlieb M, Gil S, Dinerman P, Fuchs P, Yavin E
Brain Res Mol Brain Res (23 August 2004) 127(1-2): 10-26
[Abstract@PubMed] [Authors contact]

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The LXR ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease?
Radosveta P. Koldamova, Iliya M. Lefterov, Matthias Staufenbiel, Daren Wolfe, Shaohua Huang, Joseph C. Glorioso, Michael Walter, Michael G. Roth, and John S. Lazo
J Biol Chem (22 November 2004) doi: 10.1074/jbc.M411420200
[Abstract@PubMed] [Authors contact]

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Also see NoL Noteworthy pages 2002/2003, 2004 and 2006