Increased arachidonic acid-containing phosphatidylcholine is associated with reactive microglia and astrocytes in the spinal cord after peripheral nerve injury

Xu, Dongyu; Ômura, Takao; Nio, Masaki; Arima, Hideyuki; Banno, Tomohiro; Okamoto, Ayako; Hanada, Mitsuru; Takei, Shiro; Matsushita, Shoko; Sugiyama, Eiji; Setou, Mitsutoshi; Matsuyama, Yukihiro

doi:10.1038/srep26427

Cited by 25 publications

(24 citation statements)

References 45 publications

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“…a suggested formation of GM1-bound Aβ (G-Aβ) species acting both as neuroprotective mechanism and promoting seed of Aβ aggregation [64][65][66]. Further, in line with these observations, the complementary pattern of the GM1 with the GM2/GM3 species, as well as presence of the PI, and LPI, further suggest the likely macrophage mediated lysosomal degradation of gangliosides at the plaque periphery, but not in the center of the Aβ plaques [46,67].…”

Section: Altered Gm Metabolism Is Associated With Aβ Plaque Core Formmentioning

confidence: 53%

“…In addition, to the sphingolipid species, several phosphoinositol species, including LPI and PI were detected in the peripheral, diffuse structures of cored plaques. As demonstrated by MALDI-IMS, AA containing phospholipids are essential precursors in eicosanoid synthesis underlying microglial and astroglial mediated inflammatory response mechanisms [46]. Likewise LPI, the corresponding degradation product of LPI, a process mediated by cytosolic phospholipase A2 (PLA2) activity, has been shown to regulate neuroinflammation and neurodegeneration in AD [47,48].…”

Section: Maldi-ims Highlights Aβ Plaque Associated Sphingolipid and Pmentioning

confidence: 99%

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GM1 locates to mature amyloid structures implicating a prominent role for glycolipid-protein interactions in Alzheimer pathology

Michno

Wehrli

Zetterberg

et al. 2019

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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While the molecular mechanisms underlying Alzheimer's disease remain largely unknown, abnormal accumulation and deposition of beta amyloid (Aβ) peptide into senile plaques has been identified as a critical pathological process driving disease progression. Over the last years, neuronal lipid species have been implicated in biological mechanisms underlying amyloid plaque pathology. While these processes comprise genetic features along with lipid signaling as well as direct chemical interaction of lipid species with Aβ mono-and oligomers, more efforts are needed to spatially delineate the exact lipid Aβ plaque interactions in the brain. Chemical imaging using mass spectrometry (MS) allows to probe the spatial distribution of lipid and peptide in complex biological tissues comprehensively and at high molecular specificity. As different imaging mass spectrometry (IMS) modalities provide comprehensive molecular and spatial information, we here describe a multimodal ToF SIMS-and MALDI-based IMS strategy for probing lipid and Aβ peptide changes in a transgenic mouse model of AD. Both techniques identified a general AD-associated depletion of cortical sulfatides, while multimodal MALDI IMS revealed plaque specific lipid as well as Aβ peptide isoforms in AD. In addition, MALDI IMS analysis revealed chemical features associated with morphological heterogeneity of individual Aβ deposits, where altered (?) GM1 to GM2/GM3 ganglioside metabolism was observed in the diffuse periphery of the plaques but not in the center. This was accompanied by enrichment of the Aβ1-40arc peptide in the core of these deposits. Finally, in line with these observations, likely macrophage activity as revealed by the localization of arachidonic acid (AA) conjugated phosphatidylinositols (PI) and their degradation product, lyso-phosphatidylinositols (LPI) to Aβ plaque of the PI and LPI species to the plaque periphery was demonstrated.

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Section: Altered Gm Metabolism Is Associated With Aβ Plaque Core Formmentioning

confidence: 53%

Section: Maldi-ims Highlights Aβ Plaque Associated Sphingolipid and Pmentioning

confidence: 99%

GM1 locates to mature amyloid structures implicating a prominent role for glycolipid-protein interactions in Alzheimer pathology

Michno

Wehrli

Zetterberg

et al. 2019

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…Many studies have reported a close relationship between microglial function and n-3 PUFAs since then. N-3 PUFA supplementation reduces microglial activation and/or phenotype alteration in models of brain development (Kuperstein et al, 2008;Madore et al, 2014;Abiega et al, 2016), respiratory system development (Tenorio-Lopes et al, 2017), healthy aging (Grundy et al, 2014), ischemia (Zhang et al, 2010;Belayev et al, 2011;Okabe et al, 2011;Eady et al, 2012aEady et al, ,b, 2014Chang et al, 2013;Zendedel et al, 2015;Jiang et al, 2016), spinal cord injury (Huang et al, 2007;Lim et al, 2013a,b;Paterniti et al, 2014;Tremoleda et al, 2016;Xu et al, 2016), Parkinson's disease (Muntane et al, 2010;Ji et al, 2012;Tian et al, 2015;Delattre et al, 2017;Mori et al, 2017), AD (Lynch et al, 2007;Hopperton et al, 2016;Serini and Calviello, 2016;Wen et al, 2016), systemic inflammation (Delpech et al, 2015b), traumatic brain injury (Pu et al, 2013;Harrison et al, 2015;Harvey et al, 2015;Desai et al, 2016), neuropathic pain model (Xu et al, 2013b;Manzhulo et al, 2015;Huang and Tsai, 2016), aging (Labrousse et al, 2012), demyelination (Chen et al, 2014), amyotrophic lateral sclerosis…”

Section: Microglia As a Target For N-3 Pufas And Spmsmentioning

confidence: 99%

Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology

Layé¹,

Nadjar²,

Joffre³

et al. 2017

Pharmacol Rev

313

190

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Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain.

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“…As such, we could suppose that there is a plausible link between increases in glial cell numbers and neuronal death profiles and the observations of metabolites. Supporting a facet of this, a recent study reports that the PC aa metabolites are enriched in the microglia, specifically in the spinal cord microglia after peripheral nerve injury [47] . In addition, the death of oligodendrocytes and the formation of a white-matter cyst is a key component of this model [35] .…”

Section: Time-series Analysismentioning

confidence: 72%

Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury

Blaise

Schwendimann

Chhor³

et al. 2017

Dev Neurosci

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Excitotoxicity plays a key role during insults to the developing brain such as neonatal encephalopathy, stroke, and encephalopathy of prematurity. Such insults affect many thousands of infants each year. Excitotoxicity causes frank lesions due to cell death and gliosis and disturbs normal developmental process, leading to deficits in learning, memory, and social integration that persist into adulthood. Understanding the underlying processes of the acute effects of excitotoxicity and its persistence during brain maturation provides an opportunity to identify mechanistic or diagnostic biomarkers, thus enabling and designing possible therapies. We applied mass spectrometry to provide metabolic profiles of brain tissue and plasma over time following an excitotoxic lesion (intracerebral ibotenate) to the neonatal (postnatal day 5) mouse brain. We found no differences between the plasma from the control (PBS-injected) and excitotoxic (ibotenate-injected) groups over time (on postnatal days 8, 9, 10, and 30). In the brain, we found that variations in amino acids (arginine, glutamine, phenylananine, and proline) and glycerophospholipids were sustaining acute and delayed (tertiary) responses to injury. In particular, the effect of the excitotoxic lesion on the normal profile of development was linked to alterations in a fingerprint of glycerophospolipids and amino acids. Specifically, we identified increases in the amino acids glutamine, proline, serine, threonine, tryptophan, valine, and the sphingolipid SM C26:1, and decreases in the glycerophospholipids, i.e., the arachidonic acid-containing phosphatidylcholine (PC aa) C30:2 and the PC aa C32:3. This study demonstrates that metabolic profiling is a useful approach to identify acute and tertiary effects in an excitotoxic lesion model, and generating a short list of targets with future potential in the hunt for identification, stratification, and possibly therapy.

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Increased arachidonic acid-containing phosphatidylcholine is associated with reactive microglia and astrocytes in the spinal cord after peripheral nerve injury

Cited by 25 publications

References 45 publications

GM1 locates to mature amyloid structures implicating a prominent role for glycolipid-protein interactions in Alzheimer pathology

GM1 locates to mature amyloid structures implicating a prominent role for glycolipid-protein interactions in Alzheimer pathology

Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology

Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury

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