Significance of plasma lysolecithin in patients with multiple sclerosis: a longitudinal study

Andreoli, V. M.; Maffei, Francisco H.A.; Tonon, Giancarlo; Zibetti, A

doi:10.1136/jnnp.36.4.661

Cited by 17 publications

(16 citation statements)

References 16 publications

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“…We then elucidated the nature of the soluble signal by factor removal experiments using mass spectrometry lipidomics to identify that the lipid was lysophosphatidylcholine (LPC). Our findings have been supported by previous studies where, increased LPC levels have been observed in multiple sclerosis and in aged human brain (Andreoli et al, 1973;Wender et al, 1988). However, the precise mechanism behind LPC production has not been fully elucidated.…”

Section: Discussionsupporting

confidence: 91%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

113

100

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The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.

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Section: Discussionsupporting

confidence: 91%

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Sundaram¹,

Chan²,

Poore³

et al. 2012

J. Neurosci.

113

100

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“…It is known that the demyelinating effect of LPC is due to the LPC molecule as such and not to metabolites [20]. In the case of MS, an increase in plasma levels of LPC has been reported [7], and the saturated fatty acid content of plasma LPC in MS patients is greater than that of LPC in controls [8], Whether altering the fatty acid content of patients' LPC could modify the severity of episodic demyelination re mains to be seen.…”

Section: Discussionmentioning

confidence: 99%

“…One possible candidate for such a bystander role is lysolecithin (lysophosphatidyl choline or LPC). An increase in the plasma level of LPC has been reported in MS patients [7], Furthermore, an increase in the saturated fatty acid content of LPC of MS patients compared with normal individuals has been reported [8], It is not known whether the different fatty acid content of LPC has any effect on the severity of an episode of demyelination in MS patients. We have therefore studied the myelinotoxic properties of LPC of different fatty acid composition in an animal model (the peripheral nerve of the rat), to see if lipid constitution might influence the degree of demyelin ation.…”

Section: Introductionmentioning

confidence: 99%

Influence of Fatty Acid Content of Lysophosphatidyl Choline on Its Myelinotoxic Properties

Sedal

Jennings²,

Allt³

et al. 1992

Eur Neurol

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The efficacy of lysophosphatidyl choline (LPC) type I and type IV in producing demyelination was assessed in rat tibial and sural nerve. By light and electron microscopy, a greater myelinolytic activity was demonstrated with type I, and concomitantly electrophysiology showed a more severe conduction block. In teased nerve preparations and 1-um thin sections, demyelinated fibres were more frequent with LPC type I. At 1 h after injection, electron microscopy showed much more extensive myelin lysis in the form of fine vesicular debris. By 6 days, completely demyelinated fibres were much more common and associated Schwann cells contained either small quantities or no myelin debris. With type IV LPC, cytopathological changes were more extensive at 1 h. A minority of Schwann cells showed swollen hydropic cytoplasm and degradation of organelles. Axonal retraction from the myelin sheath occurred in occasional fibres, and in a few unmyelinated fibres axoplasm showed organelle depletion and increased granularity. By 6 days, Schwann cells still contained large quantities of gross myelin debris and had often retracted to expose extensive areas of axolemma. The findings suggest that the two types of LPC have different myelinolytic actions, which may be related to their different fatty acid content. A possible role for the two types of LPC in ‘bystander demyelination’ is considered.

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“…For definitive identification, the attractant in fraction 6 was compared with enzymatically prepared 1-palmitoyl-sn-glycerol-3-phosphorylcholine (L-palmitoyl-LPtdCho), the most abundant form of LPtdCho in human plasma (15). When fraction 6 was compared with L-palmitoyl-LPtdCho at equivalent concentrations oforganic phosphorus, the attractant activities ofthe preparations for 6C3HED cells were nearly identical (Fig.…”

mentioning

confidence: 97%

Stereospecific chemoattraction of lymphoblastic cells by gradients of lysophosphatidylcholine.

Hoffman¹,

Kligerman²,

Sundt³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Human plasma contains chemoattractant activity for cultured cells from the mouse thymic lymphoma 6C3HED and also for lymphoblasts from concanavalin A-stimulated mouse spleen cells. A major portion of the attractant activity for both cell types could be attributed to plasma lysophosphatidylcholine. Studies on synthetic lysophosphatides showed that polar head group structure, acyl chain length, and stereochemical configuration are important determinants for attractant activity.Substances that cause the accumulation of lymphoid cells in sites of inflammation or control the migration of these cells through the tissues of lymphoid organs may play important roles in immune responses (1). Oriented migration (chemotaxis), increased random motility (chemokinesis), or other cellular mechanisms may cause cells to migrate toward the source of a chemoattractant gradient. t Many different substances have been reported to be chemoattractants for lymphoid cells. Among these are plasma and altered components of plasma (2), a proteolytic fragment of IgG (3), lymphokine-containing supernates from mixed lymphocyte cultures (4), lectins that are mitogenic for lymphocytes (5), a 10,500-dalton factor from immune calf thymus (6), specific antigens (2), arachidonic acid and its metabolites (7,8), and bacterial components, including staphylococcal protein A (5).In the course of studies on the attractant activity of plasma, we discovered that plasma could attract not only concanavalin A (Con A)-stimulated spleen lymphocytes but also neoplastic cells from the cultured thymic lymphoma 6C3HED. Both cell types responded similarly to plasma lipid extract and lipid fractions. Isolation and characterization of the active principle led us to conclude that much of the attractant activity in plasma could be accounted for by lysophosphatidylcholine (LPtdCho). To study the mechanism by which LPtdCho exerts its effect on lymphoid cells, we set out to define the structural requirements for molecules with attractant activity.MATERIALS AND METHODS Solvents. Organic solvents purchased from Burdick-Jackson Laboratories (Muskegon, MI) were used without further purification.Media. Cell cultures were maintained in medium A [RPMI-1640 medium supplemented with 10% (vol/vol) heat-inactivated fetal calfserum, 2 mM L-glutamine, and 100 units ofpenicillin, and 100 Mug ofstreptomycin per ml]. Medium B [minimal essential medium with Earle's salts supplemented with 0.5% bovine serum albumin (Cohn fraction V; Sigma), 70 mM sodium Hepes (pH 7.5), and 100 units ofpenicillin, and 100 Ag ofstreptomycin per ml] was used for migration assays.Migration Assay. Cell migration under agarose gels was assayed essentially as described by Nelson et al. (9). Six round glass coverslips were placed in hexagonal array in 60 X 15 mm plastic culture dishes. Four milliliters of a mixture of 5 vol of medium B and 1 vol of 80 mM sodium Hepes, pH 7.5/5% Litex LSA agarose (Accurate, Hicksville, NY) was added over the coverslips in each dish. Three wells were cut in the gel over each c...

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Significance of plasma lysolecithin in patients with multiple sclerosis: a longitudinal study

Cited by 17 publications

References 16 publications

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

Influence of Fatty Acid Content of Lysophosphatidyl Choline on Its Myelinotoxic Properties

Stereospecific chemoattraction of lymphoblastic cells by gradients of lysophosphatidylcholine.

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