Neurobiology of Lipids Noteworthy Articles

Noteworthy section of the Neurobiology of Lipids (ISSN 1683-5506) alerts interested readers about the selected noteworthy original research and viewpoint/review articles, book reviews, and meeting reports (published in other journals) on the subject of the journal scope

NoL Home | Noteworthy home | NoL Content | Archiving your research in NoL is a new service by the Neurobiology of Lipids NoL archives your research | Mission | PubMed | IFORA | Affiliates  | Contact us
For Graduate students: Assistant Editor and Research Assistant Opportunities

October 31, 2008

Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer’s disease: a tale of shotgun lipidomics
Xianlin Han
Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Address correspondence and reprint requests to Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Box 8020, 660 South Euclid Avenue, St Louis, MO 63110, USA, E-mail: xianlin@wustl.edu

AbstractShotgun lipidomics is a rapidly developing technology, which identifies and quantifies individual lipid molecular species directly from lipid extracts of biological samples. Alterations in lipid molecular species in the brain induced by neurodegenerative diseases, such as Alzheimer’s disease (AD) could provide fundamental clues to disease pathogenesis. To date, the cause(s) leading to AD pathogenesis are still unknown and apolipoprotein E (apoE) allele 4 is the only known major risk factor for this devastating disease. By utilizing shotgun lipidomics, we have recently shown that a substantial and specific depletion of sulfatide (a class of specialized myelin sphingolipids) is present in postmortem brains from subjects at the earliest clinically recognizable stage of AD. In subsequent studies to identify the biochemical mechanisms underlying sulfatide depletion at this very mild stage of AD, we have found that apoE is associated with sulfatide transport and mediates sulfatide homeostasis in the nervous system through lipoprotein metabolism pathways and that alterations in apoE-mediated sulfatide trafficking can lead to sulfatide depletion in the brain. Thus, a working model related to the potential biochemical mechanisms underlying sulfatide depletion in AD can be derived based on these results. Collectively, the results obtained from lipidomic analyses of brain samples provide important insights into the biochemical mechanisms underlying AD pathogenesis.
Keywords: Alzheimer’s disease, apolipoprotein E, electrospray ionization, lipidomics, mass spectrometry, shotgun lipidomics, sulfatide metabolism



PubMed ID and Record
Write to authors to ask them to make this article freely available at NoL Archive

N-Acetylaspartate in the CNS: From Neurodiagnostics to Neurobiology
John R. Moffett,1,2 Brian Ross,3 Peethambaran Arun,1 Chikkathur N. Madhavarao,1 and M. A. A. Namboodiri1
1 Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Building C, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
3 Magnetic Resonance Unit, Huntington Medical Research Institutes, Pasadena, CA; Rudi Schulte Research Institute, Santa Barbara CA and NARSAD
2 Contact: J.R. Moffett, phone (301) 295-9357, fax (301) 295-3566, Email: jmoffett@usuhs.mil.

AbstractThe brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.
Keywords: NAA, Canavan disease, myelination, dysmyelination, lipid synthesis, aspartoacylase, energy metabolism, N-acetyl-L-aspartic acid, acetate, acetyl coenzyme A



PubMed ID and Record
Write to authors to ask them to make this article freely available at NoL Archive
Plasticity in the Olfactory System: Lessons for the Neurobiology of Memory
D. A. WILSON, A. R. BEST, and R. M. SULLIVAN
Department of Zoology, University of Oklahoma
Address correspondence to: Donald A. Wilson, Department of Zoology, University of Oklahoma, Norman, OK 73019 (e-mail: dwilson@ou.edu).


AbstractWe are rapidly advancing toward an understanding of the molecular events underlying odor transduction, mechanisms of spatiotemporal central odor processing, and neural correlates of olfactory perception and cognition. A thread running through each of these broad components that define olfaction appears to be their dynamic nature. How odors are processed, at both the behavioral and neural level, is heavily dependent on past experience, current environmental context, and internal state. The neural plasticity that allows this dynamic processing is expressed nearly ubiquitously in the olfactory pathway, from olfactory receptor neurons to the higher-order cortex, and includes mechanisms ranging from changes in membrane excitability to changes in synaptic efficacy to neurogenesis and apoptosis. This review will describe recent findings regarding plasticity in the mammalian olfactory system that are believed to have general relevance for understanding the neurobiology of memory.
Keywords: Olfaction, Plasticity, Memory, Learning, Perception

PubMed ID and Record

August 17, 2008

Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons

Write to authors to ask them to make this article freely available at NoL Archive
Jens Brodbeck,* Maureen E. Balestra,* Ann M. Saunders,† Allen D. Roses,† Robert W. Mahley,*‡§¶‖** and Yadong Huang*‡¶**††
*Gladstone Institute of Neurological Disease and
‡Gladstone Institute of Cardiovascular Disease, The J. David Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158;
§Departments of Medicine,
¶Pathology, and
††Neurology and
‖Cardiovascular Research Institute, University of California, San Francisco, CA 94143; and
†GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709
**To whom correspondence may be addressed. E-mail: yhuang@gladstone.ucsf.edu or Email: rmahley@gladstone.ucsf.edu

PubMed ID and Record
AbstractConvergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, an insulin sensitizer and mitochondrial activator, improves cognition in patients with early or mild-to-moderate AD. Apolipoprotein (apo) E4, a major genetic risk factor for AD, exerts neuropathological effects through multiple pathways, including impairment of dendritic spine structure and mitochondrial function. Here we show that rosiglitazone significantly increased dendritic spine density in a dose-dependent manner in cultured primary cortical rat neurons. This effect was abolished by the PPAR-γ-specific antagonist, GW9662, suggesting that rosiglitazone exerts this effect by activating the PPAR-γ pathway. Furthermore, the C-terminal-truncated fragment of apoE4 significantly decreased dendritic spine density. Rosiglitazone rescued this detrimental effect. Thus, rosiglitazone might improve cognition in AD patients by increasing dendritic spine density.
Keywords: Alzheimer's disease, mitochondria, peroxisome proliferator-activated receptor-γ, apolipoprotein E fragment, synaptogenesis

Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer’s disease: a tale of shotgun lipid

Write to authors to ask them to make this article freely available at NoL Archive
Xianlin Han
Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Address correspondence and reprint requests to Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Box 8020, 660 South Euclid Avenue, St Louis, MO 63110, USA, E-mail: xianlin@wustl.edu




PubMed ID and Record

AbstractShotgun lipidomics is a rapidly developing technology, which identifies and quantifies individual lipid molecular species directly from lipid extracts of biological samples. Alterations in lipid molecular species in the brain induced by neurodegenerative diseases, such as Alzheimer’s disease (AD) could provide fundamental clues to disease pathogenesis. To date, the cause(s) leading to AD pathogenesis are still unknown and apolipoprotein E (apoE) allele 4 is the only known major risk factor for this devastating disease. By utilizing shotgun lipidomics, we have recently shown that a substantial and specific depletion of sulfatide (a class of specialized myelin sphingolipids) is present in postmortem brains from subjects at the earliest clinically recognizable stage of AD. In subsequent studies to identify the biochemical mechanisms underlying sulfatide depletion at this very mild stage of AD, we have found that apoE is associated with sulfatide transport and mediates sulfatide homeostasis in the nervous system through lipoprotein metabolism pathways and that alterations in apoE-mediated sulfatide trafficking can lead to sulfatide depletion in the brain. Thus, a working model related to the potential biochemical mechanisms underlying sulfatide depletion in AD can be derived based on these results. Collectively, the results obtained from lipidomic analyses of brain samples provide important insights into the biochemical mechanisms underlying AD pathogenesis.
Keywords: Alzheimer’s disease, apolipoprotein E, electrospray ionization, lipidomics, mass spectrometry, shotgun lipidomics, sulfatide metabolism

Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer’s disease: a tale of shotgun lipid

Write to authors to ask them to make this article freely available at NoL Archive
Xianlin Han
Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Address correspondence and reprint requests to Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Box 8020, 660 South Euclid Avenue, St Louis, MO 63110, USA, E-mail: xianlin@wustl.edu




PubMed ID and Record

AbstractShotgun lipidomics is a rapidly developing technology, which identifies and quantifies individual lipid molecular species directly from lipid extracts of biological samples. Alterations in lipid molecular species in the brain induced by neurodegenerative diseases, such as Alzheimer’s disease (AD) could provide fundamental clues to disease pathogenesis. To date, the cause(s) leading to AD pathogenesis are still unknown and apolipoprotein E (apoE) allele 4 is the only known major risk factor for this devastating disease. By utilizing shotgun lipidomics, we have recently shown that a substantial and specific depletion of sulfatide (a class of specialized myelin sphingolipids) is present in postmortem brains from subjects at the earliest clinically recognizable stage of AD. In subsequent studies to identify the biochemical mechanisms underlying sulfatide depletion at this very mild stage of AD, we have found that apoE is associated with sulfatide transport and mediates sulfatide homeostasis in the nervous system through lipoprotein metabolism pathways and that alterations in apoE-mediated sulfatide trafficking can lead to sulfatide depletion in the brain. Thus, a working model related to the potential biochemical mechanisms underlying sulfatide depletion in AD can be derived based on these results. Collectively, the results obtained from lipidomic analyses of brain samples provide important insights into the biochemical mechanisms underlying AD pathogenesis.
Keywords: Alzheimer’s disease, apolipoprotein E, electrospray ionization, lipidomics, mass spectrometry, shotgun lipidomics, sulfatide metabolism

Neurobiology of depression: an integrated view of key findings

Write to authors to ask them to make this article freely available at NoL Archive



PubMed ID and Record V Maletic,1 M Robinson,2 T Oakes,2 S Iyengar,2 S G Ball,2,3 and J Russell2

Aims
The objectives of the present review were to summarise the key findings from the clinical literature regarding the neurobiology of major depressive disorder (MDD) and their implications for maximising treatment outcomes. Several neuroanatomical structures in the prefrontal and limbic areas of the brain are involved in affective regulation. In patients with MDD, alterations in the dynamic patterns of activity among these structures have profound implications for the pathogenesis of this illness.


Discussion
The present work reviews the evidence for the progressive nature of MDD along with associated changes in neuroanatomical structure and function, especially for the hippocampus. The role of glucocorticoids, inflammatory cytokines and brain-derived growth factors are discussed as mediators of these pathological alterations. From this integrated model, the role of antidepressant therapy in restoring normative processes is examined along with additional treatment guidelines.


Conclusion
Major depressive disorder is an illness with significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain. Antidepressant pharmacotherapy is associated with restoration of the underlying physiology. Clinicians are advised to intervene with MDD using an early, comprehensive treatment approach that has remission as the goal.

May 7, 2008

Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.

Write to authors to ask them to make this article freely available at NoL Archive

Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM.

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (Abeta) deposition, a redistribution of Abeta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.
PMID: 18202749 [PubMed - indexed for MEDLINE]
PMCID: PMC2200302

PubMed ID and Record

C-terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65.

Write to authors to ask them to make this article freely available at NoL Archive

Lakshmana MK, Chen E, Yoon IS, Kang DE.

Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid beta protein (Abeta), a small peptide derived from beta- and gamma-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that the Low-density lipoprotein receptor-related protein (LRP) plays a pivotal role in the trafficking of APP and generation of Abeta. In particular, we recently showed that the soluble cytoplasmic tail of LRP (LRP-ST) without a membrane tether was sufficient to promote Abeta generation. In this study, we demonstrate that the last 37 residues of LRP cytoplasmic tail (LRP-C37) lacking the NPxY motifs and FE65 binding mediate the core pro-amyloidogenic activity of LRP-ST. Moreover, we show that the conserved dileucine motif within the LRP-C37 region is a key determinant of its Abeta promoting activity. Finally, results from a yeast 2-hybrid screen using LRP-C37 region as bait reveal 4 new LRP-binding proteins implicated in intracellular signaling and membrane protein trafficking. Our findings indicate that the LRP-C37 sequence represents a new protein-binding domain that may be useful as a therapeutic target and tool to lower Abeta generation in AD.
PMID: 18373737 [PubMed - as supplied by publisher]



PubMed ID and Record

Plasma membrane expression of the neuronal glutamate transporter EAAC1 is regulated by glial factors: Evidence for different regulatory pathways assoc

Write to authors to ask them to make this article freely available at NoL Archive

Lortet S, Canolle B, Masmejean F, Nieoullon A.

IC2N-IBDML, UMR CNRS 6216, Parc Scientifique et Technologique de Luminy, Case 907, 13288 Marseille Cedex 09, France.

At the glutamatergic synapse the neurotransmitter is removed from the synaptic cleft by high affinity amino acid transporters located on neurons (EAAC1) and astrocytes (GLAST and GLT1), and a coordinated action of these cells is necessary in order to regulate glutamate extracellular concentration. We show here that treatment of neuronal cultures with glial soluble factors (GCM) is associated with a redistribution of EAAC1 and GLAST to the cell membrane and we analysed the effect of membrane cholesterol depletion on this regulation. In enriched neuronal culture (90% neurons and 10% astrocytes), GCM treatment for 10 days increases EAAC1 and GLAST cell surface expression with no change in total expression. In opposite, GLT1 surface expression is not modified by GCM but total expression is increased. When cholesterol is acutely depleted from the membrane by 10mM methyl-beta-cyclodextrin (beta5-MCD, 30min), glutamate transport activity and cell surface expressions of EAAC1 and GLAST are decreased in the enriched neuronal culture treated by GCM. In pure neuronal culture addition of GCM also increases EAAC1 cell membrane expression but surprisingly acute treatment with beta5-MCD decreases glutamate uptake activity but not EAAC1 cell membrane expression. By immunocytochemistry a modification in the distribution of EAAC1 within neurons was undetectable whatever the treatment but we show that EAAC1 was no more co localized with Thy-1 in the enriched neuronal culture treated by GCM suggesting that GCM have stimulated polarity formation in neurons, an index of maturation. In conclusion we suggest that different regulatory mechanisms are involved after GCM treatment, glutamate transporter trafficking to and from the plasma membrane in enriched neuronal culture and modulation of EAAC1 intrinsic activity and/or association with regulatory proteins at the cell membrane in the pure neuronal culture. These different regulatory pathways of EAAC1 are associated with different neuronal maturation stages.
PMID: 18400334 [PubMed - in process]

PubMed ID and Record

Discrete roles of apoA-I and apoE in the biogenesis of HDL species: lessons learned from gene transfer studies in different mouse models.

Write to authors to ask them to make this article freely available at NoL Archive

Zannis VI, Koukos G, Drosatos K, Vezeridis A, Zanni EE, Kypreos KE, Chroni A.

Molecular Genetics, Whitaker Cardiovascular Institute, Departments of Medicine and Biochemistry, Boston University School of Medicine, Boston, MA 02118-2394, USA. vzannis@bu.edu

Using adenovirus-mediated gene transfer in apolipoprotein A-I (apoA-I)-deficient mice, we have established that apoA-I mutations inhibit discrete steps in a pathway that leads to the biogenesis and remodeling of high-density lipoprotein (HDL). To this point, five discrete categories of apoA-I mutants have been characterized that may affect the interactions of apoA-I with ATP-binding cassette superfamily A, member 1 (ABCA1) or lecithin:cholesterol acyl transferase (LCAT) or may influence the plasma phospholipid transfer protein activity or may cause various forms of dyslipidemia. Biogenesis of HDL is not a unique property of apoA-I. Using adenovirus-mediated gene transfer of apoE in apoA-I- or ABCA1-deficient mice, we have established that apolipoprotein E (apoE) also participates in a novel pathway of biogenesis of apoE-containing HDL particles. This process requires the functions of the ABCA1 lipid transporter and LCAT, and it is promoted by substitution of hydrophobic residues in the 261 to 269 region of apoE by Ala. The apoE-containing HDL particles formed in the circulation may have atheroprotective properties. ApoE-containing HDL may also have important biological functions in the brain that confer protection from Alzheimer's disease.
PMID: 18246469 [PubMed - in process]

PubMed ID and Record

Cholesterol and Clioquinol modulation of A beta(1-42) interaction with phospholipid bilayers and metals.

Write to authors to ask them to make this article freely available at NoL Archive
Lau TL, Gehman JD, Wade JD, Masters CL, Barnham KJ, Separovic F.

School of Chemistry, Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.

The beta-sheet plaques that are the most obvious pathological feature of Alzheimer's disease are composed of amyloid-beta peptides and are highly enriched in the metal ions Zn, Fe and Cu. The interaction of the full-length amyloid peptide, A beta(1-42), with phospholipid lipid bilayers was studied in the presence of the metal-chelating drug, Clioquinol (CQ). The effect of cholesterol and metal ions was also determined using solid-state 31P and 2H NMR. CQ modulated the effect of metal ions on the integrity of the bilayer and although CQ perturbed the phospholipid membrane, the bilayer integrity was maintained. Model membranes enriched in cholesterol were studied under conditions of peptide association and incorporation. Solid-state NMR showed that the bilayer integrity was preserved in cholesterol-enriched membranes in comparison to phosphatidylcholine-phosphatidylserine bilayers. Changes in peptide structure, consistent with an increase in beta-sheet, were observed using specifically 13C-labelled A beta(1-42) by magic angle spinning NMR. Results using aligned phosphatidylcholine bilayers and completely 15N-labelled peptide indicated that the peptide aggregated. The results are consistent with oligomeric beta-sheet structured peptides only partially penetrating the bilayer and cholesterol reducing the membrane disruption.
PMID: 17920561 [PubMed - indexed for MEDLINE]


PubMed ID and Record

Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease.

Write to authors to ask them to make this article freely available at NoL Archive

Zou F, Gopalraj RK, Lok J, Zhu H, Ling IF, Simpson JF, Tucker HM, Kelly JF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Bennett DA, Crook JE, Younkin SG, Estus S.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Since apoE allele status is the predominant Alzheimer's disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Recently, we identified a SNP, rs688, as modulating the splicing efficiency of low-density lipoprotein receptor (LDLR) exon 12 in female human liver and in minigene-transfected HepG2 cells. Moreover, the rs688T minor allele was associated with significantly higher LDL and total cholesterol in women within the Framingham Offspring Study cohort. Since LDLR is a major apoE receptor in the brain, we hypothesized that rs688 modulates LDLR splicing in neural tissues and associates with AD. To evaluate this hypothesis, we first transfected LDLR minigenes into SH-SY5Y neuroblastoma cells and found that the rs688T allele reduces exon 12 inclusion in this neural model. We then evaluated the association of rs688 allele with exon 12 splicing efficiency in vivo by quantifying LDLR splicing in human anterior cingulate tissue obtained at autopsy; the rs688T allele is associated with decreased LDLR exon 12 splicing efficiency in aged males, but not females. Lastly, we evaluated whether rs688 associates with AD by genotyping DNA from 1457 men and 2055 women drawn from three case-control series. The rs688T/T genotype was associated with increased AD odds in males [recessive model, odds ratio (OR) of 1.49, 95% confidence interval (CI) of 1.13-1.97, uncorrected P = 0.005], but not in females. In summary, these studies identify a functional apoE receptor SNP that is associated with AD in a sex-dependent fashion.
PMID: 18065781 [PubMed - indexed for MEDLINE]
PMCID: PMC2361153 [Available on 04/01/09]


PubMed ID and Record

Interaction with amyloid Beta Peptide compromises the lipid binding function of apolipoprotein e.

Write to authors to ask them to make this article freely available at NoL Archive
Tamamizu-Kato S, Cohen JK, Drake CB, Kosaraju MG, Drury J, Narayanaswami V.
vnarayan@chori.org.

Apolipoprotein (apo) E is an exchangeable apolipoprotein that plays an integral role in cholesterol transport in the plasma and the brain. It is also associated with protein misfolding or amyloid proteopathy of the beta amyloid peptide (Abeta) in Alzheimer's disease (AD) and cerebral amyloid angiopathy. The C-terminal domain (CT) of apoE encompasses two types of amphipathic alpha helices: a class A helix (residues 216-266) and a class G* helix (residues 273-299). This domain also harbors high-affinity lipoprotein binding and apoE self-association sites that possibly overlap. The objective of this study is to examine if the neurotoxic oligomeric Abeta interacts with apoE CT and if this association affects the lipoprotein binding function of recombinant human apoE CT. Site-specific fluorescence labeling of single cysteine-containing apoE CT variants with donor probes were employed to identify the binding of Abeta bearing an acceptor probe by intermolecular fluorescence resonance energy-transfer analysis. A higher efficiency of energy transfer was noted with probes located in the class A helix than with those located in the class G* helix of apoE CT. In addition, incubation of apoE CT with Abeta severely impaired the lipid binding ability and the overall amount of lipid-associated apoE CT. However, when apoE CT is present in a lipid-bound state, Abeta appears to be localized within the lipid milieu of the lipoprotein particle and not associated with any specific segments of the protein. When our data are taken together, they suggest that Abeta association compromises the fundamental lipoprotein binding function of apoE, which may have implications not only in terms of amyloid buildup but also in terms of the accumulation of cholesterol at extracellular sites.
PMID: 18407659 [PubMed - in process]


PubMed ID and Record

HIGH CHOLESTEROL-INDUCED NEUROINFLAMMATION AND AMYLOID PRECURSOR PROTEIN PROCESSING CORRELATE WITH LOSS OF WORKING MEMORY IN MICE.

Write to authors to ask them to make this article freely available at NoL Archive

Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR.
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer's disease (AD)-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of AD pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory (WM) load compared to counterparts receiving a control diet while the hypercholesterolemic LDLR-/- mice showed impaired WM regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR-/- mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including TNFalpha, IL-1beta, IL-6, NOS2 and COX2. There was also an induced expression of the key APP processing enzyme i.e., BACE1 in both high fat/cholesterol-fed C57BL/6 and LDLR-/- mice accompanied by an increased generation of C-terminal fragments (CTFs) of APP. Although ELISA for Abeta failed to record significant changes in the non-transgenic mice, a 3-fold increase in Abeta-40 accumulation was apparent in a strain of transgenic mice expressing wt hAPP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.
PMID: 18410513 [PubMed - as supplied by publisher]

PubMed ID and Record

Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in nor

Shea TB.
Center for Cellular Neurobiology & Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA 01854, USA. Thomas_shea@uml.edu
In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.
PMID: 17914184 [PubMed - indexed for MEDLINE]


PubMed ID and Record

May 2, 2008

Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD):

Write to authors to ask them to make this article freely available at NoL Archive

Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM.

Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, Nyby MD, Tuck ML, Frautschy SA, Cole GM.
Department of Medicine, University of California, Los Angeles, California 90095, USA.
Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer's disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate beta-amyloid (Abeta). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential omega-3 fatty acid related to reduced AD risk and reduced Abeta accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line. In vivo elevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Abeta production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD.
PMID: 18160637 [PubMed - indexed for MEDLINE]

PubMed ID and Record

April 28, 2008

test

TesWrite to authors to ask them to make this article freely available at NoL Archive
This post is a test


PubMed ID and Record

April 18, 2008

Altered Lipid Metabolism in Brain Injury and Disorders

Write to authors to ask them to make this article freely available at NoL Archive

Adibhatla RM, Hatcher JF.
Subcell Biochem. 2008;48:nihpa41041.
Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A(2) IIA and lipoprotein-PLA(2) are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A(2) attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.

PubMed ID and Record

December 31, 2007

The association study between DHCR24 polymorphisms and Alzheimer's disease

Write to authors to ask them to make this article freely available at NoL Archive

Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144(7):906-10
The association study between DHCR24 polymorphisms and Alzheimer's disease
Lamsa R, Helisalmi S, Hiltunen M, Herukka SK, Tapiola T, Pirttila T, Vepsalainen S, Soininen H.
Unit of Neurology, Clinical Department, Brain Research Unit, Clinical Research Center, Mediteknia, University of Kuopio, 70211 Kuopio, Finland. riikka.lamsa@uku.fi

DHCR24 gene in chromosome 1 encodes seladin 1, a cholesterol synthesizing enzyme. Seladin 1 protects neurons from Abeta(42) mediated toxicity and participates in regulation of Abeta(42) formation by organizing the placement of APP cleaving beta-secretase in cholesterol-rich detergent-resistant membrane domains (DRMs). In Alzheimer's disease (AD) the level of seladin 1 in affected neurons is reduced, DRMs are disorganized and Abeta(42) formation is increased. To examine genetic association of the DHCR24 with AD, we genotyped four single nucleotide polymorphism (SNP) sites (rs638944, rs600491, rs718265, and rs7374) in 414 Finnish AD cases and 459 controls and calculated the allelic and genotypic distribution of both cases and controls. The single locus association analysis indicated that men carrying the T allele of rs600491 had an increased risk of AD (OR 1.7 95% CI 1.2-2.4; P = 0.004, Bonferroni corrected P = 0.048 with 12 tests). We estimated haplotypes of SNPs rs638944 and rs600491 between cases and controls and found overall distribution of haplotypes highly significant (P < 0.001). There was a common protective haplotype TC with frequency of 0.22 in cases and 0.30 in controls (P < 0.001) and a risk haplotype GC with frequency of 0.10 in cases and 0.05 in controls (P < 0.001). We also measured CSF Abeta(42), tau and phosphorylated tau (ptau) levels in a subgroup of AD cases (n = 44) and controls (n = 10) and found that AD cases that carry rs718265 GG had lower levels of Abeta(42) than other genotype carriers. Our findings indicate that DHCR24 gene may be associated with AD risk. (c) 2007 Wiley-Liss, Inc.

PubMed ID and Record

December 29, 2007

An Apolipoprotein A-I Gene Promoter Polymorphism Associated with Cognitive Decline, but Not with Alzheimer's Disease

Write to authors to ask them to make this article freely available at NoL Archive

Dement Geriatr Cogn Disord. 2007 Dec 10;25(2):97-102
Helbecque N, Codron V, Cottel D, Amouyel P.
INSERM, U744, Institut Pasteur de Lille, Universite de Lille 2, Lille, France.

Background/Aims: Accumulating biological and epidemiological evidence suggests a close link between cholesterol metabolism and the pathophysiology of Alzheimer's disease (AD). The observation that the use of statins reduces the risk of AD sustains this hypothesis. Apolipoprotein A-I (APOA1) is the major component of the high-density lipoproteins, particles involved in reverse cholesterol transport. Therefore, genetic polymorphisms in the gene encoding APOA1 might influence cholesterol metabolism and be a risk factor for AD. A previous study suggested an impact of a G-->A polymorphism at position -75 bp in the APOA1 gene on the risk for early-onset AD and on the age at onset of the disease. We studied this polymorphism in 3 independent European population samples. Methods: Genotyping was conducted asdescribed in the previous study. Results: We were unable to show any impact of this polymorphism on the risk of AD. Conversely, subjects bearing the A allele of this polymorphism were at risk of cognitive decline. Conclusion: Our resultssuggest an impact of the G-->A polymorphism at position -75 bp in the APOA1 gene on cognitive impairment, but not on the risk of AD. Copyright (c) 2007 S. Karger AG, Basel.

PubMed ID and Record

December 28, 2007

Amyloid beta as a Regulator of Lipid Homeostasis

Write to authors to ask them to make this article freely available at NoL Archive

Trends Mol Med. 2007 Aug;13(8):337-44. Epub 2007 Jul 17
Grimm MO, Grimm HS, Hartmann T.
Universitat des Saarlandes, Kirrberger Str. 61.4, D-66421 Homburg, Germany.

The beta-amyloid peptide (A beta) is widely considered to be the molecule that causes Alzheimer's disease (AD). Besides this pathological function of A beta, recently published data reveal that A beta also has an essential physiological role in lipid homeostasis. Cholesterol increases A beta production, and conversely A beta production causes a decrease in cholesterol synthesis. The latter appears to be mediated by the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), a key enzyme in cholesterol synthesis, in an action similar to that of statins. Moreover, A beta regulates sphingolipid metabolism by directly activating sphingomyelinases (SMases). This review summarizes the molecular basis for the known physiological functions of A beta and amyloid precursor protein (APP), the roles of A beta and APP in lipid homeostasis and the medical implications of addressing lipid homeostasis in respect to AD. This knowledge might provide new insights for current and future therapeutic approaches to AD.

PubMed ID and Record

December 27, 2007

Levels of ApoE in cerebrospinal fluid are correlated with Tau and 24S-hydroxycholesterol in patients with cognitive disorders

Write to authors to ask them to make this article freely available at NoL Archive

Neurosci Lett. 2007 Sep 25;425(2):78-82. Epub 2007 Aug 15.
Shafaati M, Solomon A, Kivipelto M, Bjorkhem I, Leoni V.
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

Evidence was recently presented from in vitro studies that 24S-hydroxycholesterol acts as a signalling molecule inducing apoE-mediated cholesterol efflux from astrocytoma cells, and that there is a direct effect of the oxysterol on apoE transcription, protein synthesis and secretion. Consistent with this mechanism, a significant correlation is demonstrated here between levels of apoE and 24S-hydroxycholesterol in cerebrospinal fluid from patients with Alzheimer's disease and patients with mild cognitive impairment. Such a correlation was not found in control patients. There was no correlation between levels of apoE and cholesterol in cerebrospinal fluid from controls. The results are consistent with a close coupling between release of 24S-hydroxycholesterol and apoE secretion under conditions with neuronal degeneration. The levels of apoE in cerebrospinal fluid were also correlated to the levels of Tau and the possibility is discussed that the level of apoE in cerebrospinal fluid may be used as a marker of neurodegeneration.

PubMed ID and Record

December 26, 2007

No association of genetic variants of liver X receptor-beta with Alzheimer's disease risk

Write to authors to ask them to make this article freely available at NoL Archive

Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 14 [Epub ahead of print]
Rodriguez-Rodriguez E, Llorca J, Mateo I, Infante J, Sanchez-Quintana C, Garcia-Gorostiaga I, Fernandez-Viadero C, Pena N, Berciano J, Combarros O.
Neurology Service and Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), "Marques de Valdecilla" University Hospital (University of Cantabria), Santander, Spain.

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

PubMed ID and Record