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A Biological Perspective of CSF Lipids as Surrogate Markers for Cognitive Status in HIV

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Abstract

The development and application of biomarkers to neurodegenerative diseases has become increasingly important in clinical practice and therapeutic trials. While substantial progress has been made at the basic science level in understanding the pathophysiology of HIV-Associated Neurocognitive Disorders (HAND), there are significant limitations in our current ability to predict the onset or trajectory of disease, and to accurately determine the effects of therapeutic interventions. Thus, the development of objective biomarkers is critical to further our understanding and treatment of HAND. In recent years, biomarker discovery efforts have largely been driven forward through the implementation of multiple “omics” approaches that include (but are not restricted to): Lipidomics, proteomics, metabolomics, genomics, transcriptomics, and advances in brain imaging approaches such as functional connectomics. In this paper we summarize our progress to date on lipidomic approaches to biomarker discovery, discuss how these data have influenced basic research on the neuropathology of HAND, and implications for the development of therapeutics that target metabolic pathways involved in lipid handling.

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References

  • Achim CL, Heyes MP, Wiley CA (1993) Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J Clin Invest 91:2769–2775

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Achim CL, Adame A, Dumaop W, Everall IP, Masliah E (2009) Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J NeuroImmune Pharmacol 4:190–199

    Article  PubMed  PubMed Central  Google Scholar 

  • Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J, Kronke M (1996) FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell 86:937–947

    Article  PubMed  CAS  Google Scholar 

  • Alirezaei M, Kiosses WB, Fox HS (2008a) Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy 4:963–966

    PubMed  CAS  PubMed Central  Google Scholar 

  • Alirezaei M, Kiosses WB, Flynn CT, Brady NR, Fox HS (2008b) Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS One 3:e2906

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ances BM, Vaida F, Yeh MJ, Liang CL, Buxton RB, Letendre S, McCutchan JA, Ellis RJ (2010) HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. J Infect Dis 201:336–340

    Article  PubMed  PubMed Central  Google Scholar 

  • Andrieu-Abadie N, Levade T (2002) Sphingomyelin hydrolysis during apoptosis. Biochim Biophys Acta 1585:126–134

    Article  PubMed  CAS  Google Scholar 

  • Antinori A et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799

    Article  PubMed  CAS  Google Scholar 

  • Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Bales RA, Ethisham A, Greenberg RN, Berger JR (2004) Inflammatory changes and breakdown of microvascular integrity in early human immunodeficiency virus dementia. J Neurovirol 10:223–232

    Article  PubMed  CAS  Google Scholar 

  • Ayasolla K, Khan M, Singh AK, Singh I (2004) Inflammatory mediator and beta-amyloid (25–35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic Biol Med 37:325–338

    Article  PubMed  CAS  Google Scholar 

  • Bandaru VV, McArthur JC, Sacktor N, Cutler RG, Knapp EL, Mattson MP, Haughey NJ (2007) Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology 68:1481–1487

    Article  PubMed  CAS  Google Scholar 

  • Bandaru VV, Troncoso J, Wheeler D, Pletnikova O, Wang J, Conant K, Haughey NJ (2009) ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer’s but not normal brain. Neurobiol Aging 30:591–599

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bandaru VV, Mielke MM, Sacktor N, McArthur JC, Grant I, Letendre S, Chang L, Wojna V, Pardo C, Calabresi P, Munsaka S, Haughey NJ (2013) A lipid storage-like disorder contributes to cognitive decline in HIV-infected subjects. Neurology. doi:10.1212/WNL.0b013e3182a9565e

  • Barria A, Malinow R (2002) Subunit-specific NMDA receptor trafficking to synapses. Neuron 35:345–353

    Article  PubMed  CAS  Google Scholar 

  • Bellettato CM, Scarpa M (2010) Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:347–362

    Article  PubMed  CAS  Google Scholar 

  • Bikman BT, Summers SA (2011) Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 121:4222–4230

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Brabers NA, Nottet HS (2006) Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur J Clin Investig 36:447–458

    Article  CAS  Google Scholar 

  • Brew BJ, Bhalla RB, Paul M, Gallardo H, McArthur JC, Schwartz MK, Price RW (1990) Cerebrospinal fluid neopterin in human immunodeficiency virus type 1 infection. Ann Neurol 28:556–560

    Article  PubMed  CAS  Google Scholar 

  • Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G (2009) Neurodegeneration and ageing in the HAART era. J NeuroImmune Pharmacol 4:163–174

    Article  PubMed  Google Scholar 

  • Brugg B, Michel PP, Agid Y, Ruberg M (1996) Ceramide induces apoptosis in cultured mesencephalic neurons. J Neurochem 66:733–739

    Article  PubMed  CAS  Google Scholar 

  • Burdo TH, Soulas C, Orzechowski K, Button J, Krishnan A, Sugimoto C, Alvarez X, Kuroda MJ, Williams KC (2010) Increased monocyte turnover from bone marrow correlates with severity of SIV encephalitis and CD163 levels in plasma. PLoS Pathog 6:e1000842

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cardenas V, Meyerhoff D, Studholme C, Kornak J, Rothlind J, Lampiris H, Neuhaus J, Grant R, Chao L, Truran D, Weiner M (2009) Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy. J Neurovirol 15(4):324–333

    Google Scholar 

  • Castillo SS, Levy M, Thaikoottathil JV, Goldkorn T (2007) Reactive nitrogen and oxygen species activate different sphingomyelinases to induce apoptosis in airway epithelial cells. Exp Cell Res 313:2680–2686

    Article  PubMed  CAS  Google Scholar 

  • Chang L, Wong V, Nakama H, Watters M, Ramones D, Miller EN, Cloak C, Ernst T (2008) Greater than age-related changes in brain diffusion of HIV patients after 1 year. J NeuroImmune Pharmacol 3:265–274

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen JT, Collins DL, Freedman MS, Atkins HL, Arnold DL (2005) Local magnetization transfer ratio signal inhomogeneity is related to subsequent change in MTR in lesions and normal-appearing white-matter of multiple sclerosis patients. Neuroimage 25:1272–1278

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Hui L, Geiger NH, Haughey NJ, Geiger JD (2013) Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production. Neurobiol Aging 34:2370–2378

    Article  PubMed  CAS  Google Scholar 

  • Cheng D, Jenner AM, Shui G, Cheong WF, Mitchell TW, Nealon JR, Kim WS, McCann H, Wenk MR, Halliday GM, Garner B (2011) Lipid pathway alterations in Parkinson’s disease primary visual cortex. PLoS One 6:e17299

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Clarke CJ, Hannun YA (2006) Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim Biophys Acta 1758:1893–1901

    Article  PubMed  CAS  Google Scholar 

  • Cohen RA, Harezlak J, Gongvatana A, Buchthal S, Schifitto G, Clark U, Paul R, Taylor M, Thompson P, Tate D, Alger J, Brown M, Zhong J, Campbell T, Singer E, Daar E, McMahon D, Tso Y, Yiannoutsos CT, Navia B (2010) Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. J Neurovirol 16(6):435-444

    Google Scholar 

  • Cutler RG, Pedersen WA, Camandola S, Rothstein JD, Mattson MP (2002) Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis. Ann Neurol 52:448–457

    Article  PubMed  CAS  Google Scholar 

  • Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci U S A 101:2070–2075

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Davis CN, Tabarean I, Gaidarova S, Behrens MM, Bartfai T (2006) IL-1beta induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons. J Neurochem 98:1379–1389

    Article  PubMed  CAS  Google Scholar 

  • El-Hage N, Dever SM, Fitting S, Ahmed T, Hauser KF (2011) HIV-1 coinfection and morphine coexposure severely dysregulate hepatitis C virus-induced hepatic proinflammatory cytokine release and free radical production: increased pathogenesis coincides with uncoordinated host defenses. J Virol 85:11601–11614

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fabelo N, Martin V, Santpere G, Marin R, Torrent L, Ferrer I, Diaz M (2011) Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol Med 17:1107–1118

    PubMed  CAS  PubMed Central  Google Scholar 

  • Fensome AC, Rodrigues-Lima F, Josephs M, Paterson HF, Katan M (2000) A neutral magnesium-dependent sphingomyelinase isoform associated with intracellular membranes and reversibly inhibited by reactive oxygen species. J Biol Chem 275:1128–1136

    Article  PubMed  CAS  Google Scholar 

  • France-Lanord V, Brugg B, Michel PP, Agid Y, Ruberg M (1997) Mitochondrial free radical signal in ceramide-dependent apoptosis: a putative mechanism for neuronal death in Parkinson’s disease. J Neurochem 69:1612–1621

    Article  PubMed  CAS  Google Scholar 

  • Gelman BB (2007) The neuropathology of HIV. Handb Clin Neurol 85:301–317

    Article  PubMed  Google Scholar 

  • Gelman BB, Soukup VM, Holzer CE 3rd, Fabian RH, Schuenke KW, Keherly MJ, Richey FJ, Lahart CJ (2005) Potential role for white matter lysosome expansion in HIV-associated dementia. J Acquir Immune Defic Syndr 39:422–425

    Article  PubMed  CAS  Google Scholar 

  • Glabinski A (1993) Cytotoxic cytokines in multiple sclerosis. Neurol Neurochir Pol 27:869–875

    PubMed  CAS  Google Scholar 

  • Gongvatana A, Schweinsburg BC, Taylor MJ, Theilmann RJ, Letendre SL, Alhassoon OM, Jacobus J, Woods SP, Jernigan TL, Ellis RJ, Frank LR, Grant I (2009) White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals. J Neurovirol 15:187–195

    Article  PubMed  PubMed Central  Google Scholar 

  • Griffin DE, McArthur JC, Cornblath DR (1990) Soluble interleukin-2 receptor and soluble CD8 in serum and cerebrospinal fluid during human immunodeficiency virus-associated neurologic disease. J Neuroimmunol 28:97–109

    Article  PubMed  CAS  Google Scholar 

  • Grimaldi LM, Martino GV, Franciotta DM, Brustia R, Castagna A, Pristera R, Lazzarin A (1991) Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann Neurol 29:21–25

    Article  PubMed  CAS  Google Scholar 

  • Gu L, Huang B, Shen W, Gao L, Ding Z, Wu H, Guo J (2013) Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi. J Neuroinflammation 10:109

    Article  PubMed  PubMed Central  Google Scholar 

  • Hagberg L, Cinque P, Gisslen M, Brew BJ, Spudich S, Bestetti A, Price RW, Fuchs D (2010) Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res Ther 7:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hait NC, Oskeritzian CA, Paugh SW, Milstien S, Spiegel S (2006) Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta 1758:2016–2026

    Article  PubMed  CAS  Google Scholar 

  • Han X, Holtzman DM, McKeel DW Jr, Kelley J, Morris JC (2002) Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J Neurochem 82:809–818

    Article  PubMed  CAS  Google Scholar 

  • Haughey NJ (2010) Sphingolipids in neurodegeneration. NeuroMolecular Med 12:301–305

    Article  PubMed  CAS  Google Scholar 

  • Haughey NJ, Cutler RG, Tamara A, McArthur JC, Vargas DL, Pardo CA, Turchan J, Nath A, Mattson MP (2004) Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 55:257–267

    Article  PubMed  CAS  Google Scholar 

  • Heaton RK et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–2096

    Article  PubMed  PubMed Central  Google Scholar 

  • Hofmann K, Tomiuk S, Wolff G, Stoffel W (2000) Cloning and characterization of the mammalian brain-specific, Mg2+−dependent neutral sphingomyelinase. Proc Natl Acad Sci U S A 97:5895–5900

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hoozemans JJ, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P (2008) Cyclooxygenase-1 and -2 in the different stages of Alzheimer’s disease pathology. Curr Pharm Des 14:1419–1427

    Article  PubMed  CAS  Google Scholar 

  • Jana A, Pahan K (2004a) Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer’s disease. J Biol Chem 279:51451–51459

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jana A, Pahan K (2004b) Human immunodeficiency virus type 1 gp120 induces apoptosis in human primary neurons through redox-regulated activation of neutral sphingomyelinase. J Neurosci 24:9531–9540

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jana A, Pahan K (2007) Oxidative stress kills human primary oligodendrocytes via neutral sphingomyelinase: implications for multiple sclerosis. J NeuroImmune Pharmacol 2:184–193

    Article  PubMed  PubMed Central  Google Scholar 

  • Jana A, Hogan EL, Pahan K (2009) Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci 278:5–15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jaturapatporn D, Isaac MG, McCleery J, Tabet N (2012) Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 2, CD006378

    PubMed  Google Scholar 

  • Ju TC, Chen SD, Liu CC, Yang DI (2005) Protective effects of S-nitrosoglutathione against amyloid beta-peptide neurotoxicity. Free Radic Biol Med 38:938–949

    Article  PubMed  CAS  Google Scholar 

  • Kalvodova L, Kahya N, Schwille P, Ehehalt R, Verkade P, Drechsel D, Simons K (2005) Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem 44:36815–36823

    Google Scholar 

  • Kamat A, Lyons JL, Misra V, Uno H, Morgello S, Singer EJ, Gabuzda D (2012) Monocyte activation markers in cerebrospinal fluid associated with impaired neurocognitive testing in advanced HIV infection. J Acquir Immune Defic Syndr 60:234–243

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Karplus TM, Saag KG (1998) Nonsteroidal anti-inflammatory drugs and cognitive function: do they have a beneficial or deleterious effect? Drug Saf Int J Med Toxicol Drug Exper 19:427–433

    Article  CAS  Google Scholar 

  • Khanlou N, Moore DJ, Chana G, Cherner M, Lazzaretto D, Dawes S, Grant I, Masliah E, Everall IP (2009) Increased frequency of alpha-synuclein in the substantia nigra in human immunodeficiency virus infection. J Neurovirol 15:131–138

    Article  PubMed  CAS  Google Scholar 

  • Kim S, Steelman AJ, Zhang Y, Kinney HC, Li J (2012) Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury. Brain Pathol 22:41–57

    Article  PubMed  CAS  Google Scholar 

  • Kroemer G, Jaattela M (2005) Lysosomes and autophagy in cell death control. Nat Rev Cancer 5:886–897

    Article  PubMed  CAS  Google Scholar 

  • Lavezzari G, McCallum J, Dewey CM, Roche KW (2004) Subunit-specific regulation of NMDA receptor endocytosis. J Neurosci 24:6383–6391

    Article  PubMed  CAS  Google Scholar 

  • Lee YJ, Wang S, Slone SR, Yacoubian TA, Witt SN (2011) Defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson’s disease. PLoS One 6:e15946

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Levy M, Castillo SS, Goldkorn T (2006) nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis. Biochem Biophys Res Commun 344:900–905

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Hannun YA (1997) Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 272:16281–16287

    Article  PubMed  CAS  Google Scholar 

  • Luzio JP, Pryor PR, Bright NA (2007) Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8:622–632

    Article  PubMed  CAS  Google Scholar 

  • Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E (2004) Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 81:70–73

    Article  PubMed  CAS  Google Scholar 

  • Malaplate-Armand C, Florent-Bechard S, Youssef I, Koziel V, Sponne I, Kriem B, Leininger-Muller B, Olivier JL, Oster T, Pillot T (2006) Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis 23:178–189

    Article  PubMed  CAS  Google Scholar 

  • Marker DF, Tremblay ME, Puccini JM, Barbieri J, Gantz Marker MA, Loweth CJ, Muly EC, Lu SM, Goodfellow VS, Dewhurst S, Gelbard HA (2013) The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders. J Neurosci 33:9998–10010

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Martinez TN, Chen X, Bandyopadhyay S, Merrill AH, Tansey MG (2012) Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons. Mol Neurodegener 7:45

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • McArthur JC, Nance-Sproson TE, Griffin DE, Hoover D, Selnes OA, Miller EN, Margolick JB, Cohen BA, Farzadegan H, Saah A (1992) The diagnostic utility of elevation in cerebrospinal fluid beta 2-microglobulin in HIV-1 dementia. Multicenter AIDS Cohort Study. Neurology 42:1707–1712

    Article  PubMed  CAS  Google Scholar 

  • McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67:699–714

    PubMed  CAS  Google Scholar 

  • McMurtray A, Nakamoto B, Shikuma C, Valcour V (2008) Cortical atrophy and white matter hyperintensities in HIV: the Hawaii Aging with HIV Cohort Study. J Stroke Cerebrovasc Dis 17:212–217

    Article  PubMed  PubMed Central  Google Scholar 

  • Mencarelli C, Martinez-Martinez P (2013) Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70:181–203

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mielke MM, Haughey NJ, Ratnam Bandaru VV, Schech S, Carrick R, Carlson MC, Mori S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG (2010) Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss. Alzheimers Dement 6:378–385

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Narayanan S, Francis SJ, Sled JG, Santos AC, Antel S, Levesque I, Brass S, Lapierre Y, Sappey-Marinier D, Pike GB, Arnold DL (2006) Axonal injury in the cerebral normal-appearing white matter of patients with multiple sclerosis is related to concurrent demyelination in lesions but not to concurrent demyelination in normal-appearing white matter. Neuroimage 29:637–642

    Article  PubMed  Google Scholar 

  • Nguyen TP, Soukup VM, Gelman BB (2010) Persistent hijacking of brain proteasomes in HIV-associated dementia. Am J Pathol 176:893–902

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Nixon GF (2009) Sphingolipids in inflammation: pathological implications and potential therapeutic targets. Br J Pharmacol 158:982–993

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Nixon RA, Yang DS, Lee JH (2008) Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4:590–599

    PubMed  CAS  Google Scholar 

  • Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, Salter MW (2003) Glycine binding primes NMDA receptor internalization. Nature 422:302–307

    Article  PubMed  CAS  Google Scholar 

  • Novgorodov SA, Gudz TI (2011) Ceramide and mitochondria in ischemic brain injury. Int J Biochem Mol Biol 2:347–361

    PubMed  CAS  PubMed Central  Google Scholar 

  • Pelle MT, Bazille C, Gray F (2008) Neuropathology and HIV dementia. Handb Clin Neurol 89:807–818

    Article  PubMed  Google Scholar 

  • Portegies P, Godfried MH, Hintzen RQ, Stam J, van der Poll T, Bakker M, van Deventer SJ, van Lier RA, Goudsmit J (1993) Low levels of specific T cell activation marker CD27 accompanied by elevated levels of markers for non-specific immune activation in the cerebrospinal fluid of patients with AIDS dementia complex. J Neuroimmunol 48:241–247

    Article  PubMed  CAS  Google Scholar 

  • Porwit A, Parravicini C, Petren AL, Barkhem T, Costanzi G, Josephs S, Biberfeld P (1989) Cell association of HIV in AIDS-related encephalopathy and dementia. APMIS 97:79–90

    Article  PubMed  CAS  Google Scholar 

  • Puglielli L, Ellis BC, Saunders AJ, Kovacs DM (2003) Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. J Biol Chem 278:19777–19783

    Article  PubMed  CAS  Google Scholar 

  • Roberts TK, Eugenin EA, Morgello S, Clements JE, Zink MC, Berman JW (2010) PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation. Am J Pathol 177:1848–1860

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Roche KW, Standley S, McCallum J, Dune Ly C, Ehlers MD, Wenthold RJ (2001) Molecular determinants of NMDA receptor internalization. Nat Neurosci 4:794–802

    Article  PubMed  CAS  Google Scholar 

  • Saas P, Boucraut J, Quiquerez AL, Schnuriger V, Perrin G, Desplat-Jego S, Bernard D, Walker PR, Dietrich PY (1999) CD95 (Fas/Apo-1) as a receptor governing astrocyte apoptotic or inflammatory responses: a key role in brain inflammation? J Immunol 162:2326–2333

    PubMed  CAS  Google Scholar 

  • Sachse M, Ramm G, Strous G, Klumperman J (2002) Endosomes: multipurpose designs for integrating housekeeping and specialized tasks. Histochem Cell Biol 117:91–104

    Article  PubMed  CAS  Google Scholar 

  • Sacktor N, Haughey N, Cutler R, Tamara A, Turchan J, Pardo C, Vargas D, Nath A (2004) Novel markers of oxidative stress in actively progressive HIV dementia. J Neuroimmunol 157:176–184

    Article  PubMed  CAS  Google Scholar 

  • Satoi H, Tomimoto H, Ohtani R, Kitano T, Kondo T, Watanabe M, Oka N, Akiguchi I, Furuya S, Hirabayashi Y, Okazaki T (2005) Astroglial expression of ceramide in Alzheimer’s disease brains: a role during neuronal apoptosis. Neuroscience 130:657–666

    Article  PubMed  CAS  Google Scholar 

  • Schwandner R, Wiegmann K, Bernardo K, Kreder D, Kronke M (1998) TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 273:5916–5922

    Article  PubMed  CAS  Google Scholar 

  • Scott DB, Michailidis I, Mu Y, Logothetis D, Ehlers MD (2004) Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals. J Neurosci 24:7096–7109

    Article  PubMed  CAS  Google Scholar 

  • Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, Schifitto G, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Epstein LG, Marder K (2004) Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 63:2084–2090

    Article  PubMed  CAS  Google Scholar 

  • Shen D, Wang X, Li X, Zhang X, Yao Z, Dibble S, Dong XP, Yu T, Lieberman AP, Showalter HD, Xu H (2012) Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun 3:731

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Singh I, Pahan K, Khan M, Singh AK (1998) Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem 273:20354–20362

    Article  PubMed  CAS  Google Scholar 

  • Sugaya K, Uz T, Kumar V, Manev H (2000) New anti-inflammatory treatment strategy in Alzheimer’s disease. Jpn J Pharmacol 82:85–94

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Liou B, Ran H, Skelton MR, Williams MT, Vorhees CV, Kitatani K, Hannun YA, Witte DP, Xu YH, Grabowski GA (2010) Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Hum Mol Genet 19:1088–1097

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tabatadze N, Savonenko A, Song H, Bandaru VV, Chu M, Haughey NJ (2010) Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. J Neurosci Res 88:2940–2951

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tomiuk S, Hofmann K, Nix M, Zumbansen M, Stoffel W (1998) Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proc Natl Acad Sci U S A 95:3638–3643

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tozzi V, Balestra P, Bellagamba R, Corpolongo A, Salvatori MF, Visco-Comandini U, Vlassi C, Giulianelli M, Galgani S, Antinori A, Narciso P (2007) Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr 45:174–182

    Article  PubMed  Google Scholar 

  • Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E (2008) Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones. Br J Pharmacol 153:775–783

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE (1992) Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol 31:349–360

    Article  PubMed  CAS  Google Scholar 

  • Valcour V, Watters MR, Williams AE, Sacktor N, McMurtray A, Shikuma C (2008) Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy. J Neurovirol 14:362–367

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van het Hof B, Kooij G, Reijerkerk A, Dijkstra C, van van der Valk P, van Horssen J, de Vries HE (2013) Fingolimod attenuates ceramide-induced blood–brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathol 124:397–410

    Article  CAS  Google Scholar 

  • van Echten-Deckert G, Walter J (2012) Sphingolipids: critical players in Alzheimer’s disease. Prog Lipid Res 51:378–393

    Article  PubMed  CAS  Google Scholar 

  • Visnjic D, Batinic D, Banfic H (1999) Different roles of protein kinase C alpha and delta isoforms in the regulation of neutral sphingomyelinase activity in HL-60 cells. Biochem J 344(Pt 3):921–928

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wahl SM, Allen JB, McCartney-Francis N, Morganti-Kossmann MC, Kossmann T, Ellingsworth L, Mai UE, Mergenhagen SE, Orenstein JM (1991) Macrophage- and astrocyte-derived transforming growth factor beta as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome. J Exp Med 173:981–991

    Article  PubMed  CAS  Google Scholar 

  • Washbourne P, Liu XB, Jones EG, McAllister AK (2004) Cycling of NMDA receptors during trafficking in neurons before synapse formation. J Neurosci 24:8253–8264

    Article  PubMed  CAS  Google Scholar 

  • Weed M, Adams RJ, Hienz RD, Meulendyke KA, Linde ME, Clements JE, Mankowski JL, Zink MC (2012) SIV/macaque model of HIV infection in cocaine users: minimal effects of cocaine on behavior, virus replication, and CNS inflammation. J NeuroImmune Pharmacol 7:401–411

    Article  PubMed  PubMed Central  Google Scholar 

  • Wesselingh SL, Power C, Glass JD, Tyor WR, McArthur JC, Farber JM, Griffin JW, Griffin DE (1993) Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol 33:576–582

    Article  PubMed  CAS  Google Scholar 

  • Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ (2008) A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain 131:3092–3102

    Article  PubMed  PubMed Central  Google Scholar 

  • Wheeler D, Knapp E, Bandaru VV, Wang Y, Knorr D, Poirier C, Mattson MP, Geiger JD, Haughey NJ (2009) Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. J Neurochem 109:1237–1249

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wigdahl B, Kunsch C (1989) Role of HIV in human nervous system dysfunction. AIDS Res Hum Retrovir 5:369–374

    Article  PubMed  CAS  Google Scholar 

  • Wiley CA, Achim CL, Schrier RD, Heyes MP, McCutchan JA, Grant I (1992) Relationship of cerebrospinal fluid immune activation associated factors to HIV encephalitis. Aids 6:1299–1307

    Article  PubMed  CAS  Google Scholar 

  • Worgall TS (2011) Sphingolipid synthetic pathways are major regulators of lipid homeostasis. Adv Exp Med Biol 721:139–148

    Article  PubMed  CAS  Google Scholar 

  • Xu H, Bae M, Tovar YRLB, Patel N, Bandaru VV, Pomerantz D, Steiner JP, Haughey NJ (2011) The human immunodeficiency virus coat protein gp120 promotes forward trafficking and surface clustering of NMDA receptors in membrane microdomains. J Neurosci 31:17074–17090

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Yilmaz A, Yiannoutsos CT, Fuchs D, Price RW, Crozier K, Hagberg L, Spudich S, Gisslen M (2013) Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 10:62

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Li X, Becker KA, Gulbins E (2009) Ceramide-enriched membrane domains–structure and function. Biochim Biophys Acta 1788:178–183

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by National Institutes of Health grants MH077542, MH075673, AG034849, and MH096636

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The authors have no conflicts of interest related to this work to report.

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Correspondence to Norman J. Haughey.

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Haughey, N.J., Zhu, X. & Bandaru, V.V.R. A Biological Perspective of CSF Lipids as Surrogate Markers for Cognitive Status in HIV. J Neuroimmune Pharmacol 8, 1136–1146 (2013). https://doi.org/10.1007/s11481-013-9506-0

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