CoChat
Sign Up
Cited by 124Fatty Acid Research and HealthNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Docosahexaenoic acid (DHA): a modulator of microglia activity and dendritic spine morphology

Open access
Chang, Philip K-Y, Khatchadourian, Armen, McKinney, Rebecca Anne, Maysinger, Dusica·2015·Journal of Neuroinflammation
DOI 10.1186/s12974-015-0244-5PMC PMC4344754
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Recent studies have revealed that excessive activation of microglia and inflammation-mediated neurotoxicity are implicated in the progression of several neurological disorders. In particular, chronic inflammation in vivo and exposure of cultured brain cells to lipopolysaccharide (LPS) in vitro can adversely change microglial morphology and function. This can have both direct and indirect effects on synaptic structures and functions. The integrity of dendritic spines, the postsynaptic component of excitatory synapses, dictates synaptic efficacy. Interestingly, dysgenesis of dendritic spines has been found in many neurological diseases associated with ω-3 polyunsaturated fatty acid (PUFA) deficiency and cognitive decline. In contrast, supplemented ω-3 PUFAs, such as docosahexaenoic acid (DHA), can partly correct spine defects. Hence, we hypothesize that DHA directly affects synaptic integrity and indirectly through neuron-glia interaction. Strong activation of microglia by LPS is accompanied by marked release of nitric oxide and formation of lipid bodies (LBs), both dynamic biomarkers of inflammation. Here we investigated direct effects of DHA on synaptic integrity and its indirect effects via microglia in the hippocampal CA1 region. METHODS: Microglia (N9) and organotypic hippocampal slice cultures were exposed to the proinflammagen LPS (100 ng/ml) for 24 h. Biochemical and morphological markers of inflammation were investigated in microglia and CA1 regions of hippocampal slices. As biomarkers of hyperactive microglia, mitochondrial function, nitric oxide release and LBs (number, size, LB surface-associated proteins) were assessed. Changes in synaptic transmission of CA1 pyramidal cells were determined following LPS and DHA (25-50 μM) treatments by recording spontaneous AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs). RESULTS: Microglia responded to LPS stimulation with a significant decrease of mitochondrial function, increased nitric oxide production and an increase in the formation of large LBs. LPS treatment led to a significant reduction of dendritic spine densities and an increase in the AMPA-mediated mEPSC inter-event interval (IEI). DHA normalized the LPS-induced abnormalities in both neurons and microglia, as revealed by the restoration of synaptic structures and functions in hippocampal CA1 pyramidal neurons. CONCLUSION: Our findings indicate that DHA can prevent LPS-induced abnormalities (neuroinflammation) by reducing inflammatory biomarkers, thereby normalizing microglia activity and their effect on synaptic function.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12974-015-0244-5

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 68

  1. [1]Salter Michael W Beggs S Sublime microglia: expanding roles for the guardians of the CNS Cell 2014 158 15 24 10.1016/j.cell.2014.06.008 24995975 · DOI · Paper page
  2. [2]Galland L Diet and inflammation Nutr Clin Pract 2010 25 634 40 10.1177/0884533610385703 21139128 · DOI
  3. [4]Raederstorff D Pantze M Bachmann H Moser U Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation Int Arch Allergy Immunol 1996 111 284 90 10.1159/000237379 8917124 · DOI
  4. [6]Innis SM Dietary (n-3) fatty acids and brain development J Nutr 2007 137 855 9 17374644
  5. [7]Dyall SC Michael-Titus AT Neurological benefits of omega-3 fatty acids Neuromolecular Med 2008 10 219 35 10.1007/s12017-008-8036-z 18543124 · DOI
  6. [8]Hartmann T van Wijk N Wurtman RJ Olde Rikkert MGM Sijben JWC Soininen H A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer’s disease J Alzheimer’s Dis 2014 41 715 7 24898653
  7. [9]Cansev M Wurtman RJ Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils Neuroscience 2007 148 421 31 10.1016/j.neuroscience.2007.06.016 17683870 PMC2048660 · DOI
  8. [10]Cole GM Ma Q-L Frautschy SA Omega-3 fatty acids and dementia Prostaglandins Leukot Essent Fatty Acids 2009 81 213 21 10.1016/j.plefa.2009.05.015 19523795 PMC4019002 · DOI
  9. [11]Berson EL Rosner B Sandberg MA Weigel-DiFranco C Moser A Brockhurst RJ Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin a treatment Arch Ophthalmol 2004 122 1297 305 10.1001/archopht.122.9.1297 15364708 · DOI
  10. [12]Quinn JF Raman R Thomas RG Yurko-Mauro K Nelson EB Van Dyck C Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial JAMA 2010 304 1903 11 10.1001/jama.2010.1510 21045096 PMC3259852 · DOI · Paper page
  11. [14]Hughes V Microglia: the constant gardeners Nature 2012 485 570 2 10.1038/485570a 22660301 · DOI
  12. [17]Nimmerjahn A Kirchhoff F Helmchen F Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo Science 2005 308 1314 8 10.1126/science.1110647 15831717 · DOI · Paper page
  13. [19]Wake H Moorhouse AJ Jinno S Kohsaka S Nabekura J Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals J Neurosci 2009 29 3974 80 10.1523/JNEUROSCI.4363-08.2009 19339593 PMC6665392 · DOI · Paper page
  14. [21]Tremblay M-È Stevens B Sierra A Wake H Bessis A Nimmerjahn A The role of microglia in the healthy brain J Neurosci 2011 31 16064 9 10.1523/JNEUROSCI.4158-11.2011 22072657 PMC6633221 · DOI · Paper page
  15. [22]Nakamura Y Si QS Kataoka K Lipopolysaccharide-induced microglial activation in culture: temporal profiles of morphological change and release of cytokines and nitric oxide Neurosci Res 1999 35 95 100 10.1016/S0168-0102(99)00071-1 10616913 · DOI
  16. [24]Hanisch U-K Johnson TV Kipnis J Toll-like receptors: roles in neuroprotection? Trends Neurosci 2008 31 176 82 10.1016/j.tins.2008.01.005 18329736 · DOI
  17. [25]Martin S Parton RG Lipid droplets: a unified view of a dynamic organelle Nat Rev Mol Cell Biol 2006 7 373 8 10.1038/nrm1912 16550215 · DOI
  18. [26]Farese RV Walther TC Lipid droplets finally get a little r-e-s-p-e-c-t Cell 2009 139 855 60 10.1016/j.cell.2009.11.005 19945371 PMC3097139 · DOI
  19. [27]Murphy S Martin S Parton RG Lipid droplet-organelle interactions; sharing the fats BBA - Mol Cell Biol L 2009 1791 441 7 18708159
  20. [28]Lecchi C Invernizzi G Agazzi A Modina S Sartorelli P Savoini G Effects of EPA and DHA on lipid droplet accumulation and mRNA abundance of pat proteins in caprine monocytes Res Vet Sci 2013 94 246 51 10.1016/j.rvsc.2012.09.019 23102647 · DOI
  21. [29]McKinney RA Physiological roles of spine motility: development, plasticity and disorders Biochem Soc Trans 2005 33 1299 302 10.1042/BST20051299 16246103 · DOI
  22. [30]McKinney RA Excitatory amino acid involvement in dendritic spine formation, maintenance and remodelling J Physiol 2010 588 107 16 10.1113/jphysiol.2009.178905 19933758 PMC2821552 · DOI
  23. [31]McKinney RA Thompson SM Squire LR Glutamate regulation of dendritic spine form and function Encyclopedia of neuroscience 2009 Oxford Academic 905 11
  24. [33]Sala C Segal M Dendritic spines: the locus of structural and functional plasticity Physiol Rev 2014 94 141 88 10.1152/physrev.00012.2013 24382885 · DOI
  25. [34]Harris KM Weinberg RJ Ultrastructure of synapses in the mammalian brain Cold Spring Harb Perspect Biol 2012 4 1 30 10.1101/cshperspect.a005587 PMC3331701 22357909 · DOI
  26. [36]Bourne J Harris KM Do thin spines learn to be mushroom spines that remember? Curr Opin Neurobiol 2007 17 381 6 10.1016/j.conb.2007.04.009 17498943 · DOI · Paper page
  27. [38]Lai K-O Ip NY Structural plasticity of dendritic spines: the underlying mechanisms and its dysregulation in brain disorders BBA - Mol Basis Dis 2013 1832 2257 63 10.1016/j.bbadis.2013.08.012 24012719 · DOI
  28. [39]Pozueta J Lefort R Shelanski ML Synaptic changes in Alzheimer’s disease and its models Neuroscience 2013 251 51 65 10.1016/j.neuroscience.2012.05.050 22687952 · DOI
  29. [41]Gähwiler BH Capogna M Debanne D McKinney RA Thompson SM Organotypic slice cultures: a technique has come of age Trends Neurosci 1997 20 471 7 10.1016/S0166-2236(97)01122-3 9347615 · DOI
  30. [42]Chang PKY Boridy S McKinney RA Maysinger D Letrozole potentiates mitochondrial and dendritic spine impairments induced by β-amyloid J Aging Res 2013 2013 1 11 10.1155/2013/538979 PMC3730361 23956860 · DOI
  31. [43]Bulankina AV Deggerich A Wenzel D Mutenda K Wittmann JG Rudolph MG TIP47 functions in the biogenesis of lipid droplets J Cell Biol 2009 185 641 55 10.1083/jcb.200812042 19451273 PMC2711566 · DOI
  32. [44]Imamura M Inoguchi T Ikuyama S Taniguchi S Kobayashi K Nakashima N ADRP stimulates lipid accumulation and lipid droplet formation in murine fibroblasts Am J Physiol Endocrinol Metab 2002 283 E775 83 12217895
  33. [45]Feingold KR Kazemi MR Magra AL McDonald CM Chui LG Shigenaga JK ADRP/ADFP and Mal1 expression are increased in macrophages treated with tlr agonists Atherosclerosis 2010 209 81 8 10.1016/j.atherosclerosis.2009.08.042 19748622 · DOI
  34. [46]Khatchadourian A Bourque SD Richard VR Titorenko VI Maysinger D Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia BBA - Mol Cell Biol L 2012 1821 607 17 22289388
  35. [47]Jägerström S Polesie S Wickström Y Johansson BR Schröder HD Højlund K Lipid droplets interact with mitochondria using Snap23 Cell Biol Int 2009 33 934 40 10.1016/j.cellbi.2009.06.011 19524684 · DOI
  36. [48]Goodman JM The gregarious lipid droplet J Biol Chem 2008 283 28005 9 10.1074/jbc.R800042200 18611863 PMC2568941 · DOI
  37. [49]Orr SK Trépanier M-O Bazinet RP N-3 polyunsaturated fatty acids in animal models with neuroinflammation Prostaglandins Leukot Essent Fatty Acids (PLEFA) 2013 88 97 103 10.1016/j.plefa.2012.05.008 22770766 · DOI
  38. [50]Aguzzi A Barres BA Bennett ML Microglia: scapegoat, saboteur, or something else? Science 2013 339 156 61 10.1126/science.1227901 23307732 PMC4431634 · DOI · Paper page
  39. [51]Kettenmann H Hanisch U-K Noda M Verkhratsky A Physiology of microglia Physiol Rev 2011 91 461 553 10.1152/physrev.00011.2010 21527731 · DOI · Paper page
  40. [52]Goings GE Kozlowski DA Szele FG Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain Glia 2006 54 329 42 10.1002/glia.20381 16862532 · DOI
  41. [53]Hanisch U-K Kettenmann H Microglia: active sensor and versatile effector cells in the normal and pathologic brain Nat Neurosci 2007 10 1387 94 10.1038/nn1997 17965659 · DOI · Paper page
  42. [54]Gurley C Nichols J Liu S Phulwani NK Esen N Kielian T Microglia and astrocyte activation by toll-like receptor ligands: modulation by PPAR- agonists PPAR Res 2008 2008 15 10.1155/2008/453120 PMC2435222 18584038 · DOI
  43. [55]Schafer DP Lehrman EK Stevens B The “quad-partite” synapse: microglia-synapse interactions in the developing and mature cns Glia 2013 61 24 36 10.1002/glia.22389 22829357 PMC4082974 · DOI · Paper page
  44. [57]Stephan AH Barres BA Stevens B The complement system: an unexpected role in synaptic pruning during development and disease Annu Rev Neurosci 2012 35 369 89 10.1146/annurev-neuro-061010-113810 22715882 · DOI · Paper page
  45. [58]Stevens B Allen NJ Vazquez LE Howell GR Christopherson KS Nouri N The classical complement cascade mediates CNS synapse elimination Cell 2007 131 1164 78 10.1016/j.cell.2007.10.036 18083105 · DOI · Paper page
  46. [59]Guo Y Cordes KR Farese RV Walther TC Lipid droplets at a glance J Cell Sci 2009 122 749 52 10.1242/jcs.037630 19261844 PMC2714424 · DOI
  47. [60]Khatchadourian A Maysinger D Lipid droplets: their role in nanoparticle-induced oxidative stress Mol Pharm 2009 6 1125 37 10.1021/mp900098p 19445477 · DOI
  48. [61]Yang H Galea A Sytnyk V Crossley M Controlling the size of lipid droplets: lipid and protein factors Curr Opin Cell Biol 2012 24 509 16 10.1016/j.ceb.2012.05.012 22726586 · DOI
  49. [62]Chen CT Trepanier M-O Hopperton KE Domenichiello AF Masoodi M Bazinet RP Inhibiting mitochondrial [beta]-oxidation selectively reduces levels of nonenzymatic oxidative polyunsaturated fatty acid metabolites in the brain J Cereb Blood Flow Metab 2014 34 376 9 10.1038/jcbfm.2013.221 24326387 PMC3948125 · DOI
  50. [63]Serhan CN Pro-resolving lipid mediators are leads for resolution physiology Nature 2014 510 92 101 10.1038/nature13479 24899309 PMC4263681 · DOI · Paper page
  51. [64]Lafourcade M Larrieu T Mato S Duffaud A Sepers M Matias I Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions Nat Neurosci 2011 14 345 50 10.1038/nn.2736 21278728 · DOI
  52. [66]Talukdar S Olefsky JM Osborn O Targeting GPR120 and other fatty acid-sensing gpcrs ameliorates insulin resistance and inflammatory diseases Trends Pharmacol Sci 2011 32 543 50 10.1016/j.tips.2011.04.004 21663979 PMC3419590 · DOI
  53. [67]Calon F Lim GP Yang F Morihara T Teter B Ubeda O Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model Neuron 2004 43 633 45 10.1016/j.neuron.2004.08.013 15339646 PMC2442162 · DOI · Paper page
  54. [68]Calon F Lim GP Morihara T Yang F Ubeda O Salem N Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases nmda receptors in the brain of a transgenic mouse model of Alzheimer’s disease Eur J Neurosci 2005 22 617 26 10.1111/j.1460-9568.2005.04253.x 16101743 · DOI
  55. [69]Bazinet RP Laye S Polyunsaturated fatty acids and their metabolites in brain function and disease Nat Rev Neurosci 2014 15 771 85 10.1038/nrn3820 25387473 · DOI
  56. [70]Rao JS Ertley RN Lee HJ DeMar JC Jr Arnold JT Rapoport SI N-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex bdnf via a p38 MAPK-dependent mechanism Mol Psychiatry 2006 12 36 46 10.1038/sj.mp.4001888 16983391 · DOI
  57. [71]Bazan NG Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection Curr Opin Clin Nutr Metab Care 2007 10 136 41 10.1097/MCO.0b013e32802b7030 17285000 · DOI
  58. [72]Cole GM Frautschy SA DHA may prevent age-related dementia J Nutr 2010 140 869 74 10.3945/jn.109.113910 20181786 PMC2838628 · DOI
  59. [73]Picq M Chen P Perez M Michaud M Véricel E Guichardant M DHA metabolism: targeting the brain and lipoxygenation Mol Neurobiol 2010 42 48 51 10.1007/s12035-010-8131-7 20422316 PMC2894371 · DOI
  60. [74]Bibel M Barde Y-A Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system Genes Dev 2000 14 2919 37 10.1101/gad.841400 11114882 · DOI
  61. [75]Wu A Ying Z Gomez-Pinilla F Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats J Neurotrauma 2004 21 1457 67 10.1089/neu.2004.21.1457 15672635 · DOI · Paper page
  62. [76]Zhao M Zhou A Xu L Zhang X The role of TLR4-mediated PTEN/PI3K/AKT/NF-κB signaling pathway in neuroinflammation in hippocampal neurons Neuroscience 2014 269 93 101 10.1016/j.neuroscience.2014.03.039 24680857 · DOI
  63. [77]Sheng Z-H Cai Q Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration Nat Rev Neurosci 2012 13 77 93 10.1038/nrg3141 22218207 PMC4962561 · DOI · Paper page
  64. [78]Tyurina YY Poloyac SM Tyurin VA Kapralov AA Jiang J Anthonymuthu TS Mitochondrial pathway for biosynthesis of lipid mediators Nat Chem 2014 6 542 52 10.1038/nchem.1924 24848241 PMC4201180 · DOI
  65. [79]Flis VV Daum G Lipid transport between the endoplasmic reticulum and mitochondria Cold Spring Harb Perspect Biol 2013 5 1 22 10.1101/cshperspect.a013235 PMC3660828 23732475 · DOI
  66. [80]Cosentino K García-Sáez AJ Mitochondrial alterations in apoptosis Chem Phys Lipids 2014 181 62 75 10.1016/j.chemphyslip.2014.04.001 24732580 · DOI
  67. [81]Ren M Phoon CKL Schlame M Metabolism and function of mitochondrial cardiolipin Prog Lipid Res 2014 55 1 16 10.1016/j.plipres.2014.04.001 24769127 · DOI
  68. [83]Mapstone M Cheema AK Fiandaca MS Zhong X Mhyre TR MacArthur LH Plasma phospholipids identify antecedent memory impairment in older adults Nat Med 2014 20 415 8 10.1038/nm.3466 24608097 PMC5360460 · DOI

Cited by

Sorted by citations

Authors
Chang, P. K.-Y., Khatchadourian, A., McKinney, R. A., & Maysinger, D.
Affiliations
McGill University (CA)
Corresponding author
McKinney, Rebecca Anne
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2015-02-22
Volume
12
Issue
1
Pages
34-34
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-015-0244-5
PMC
PMC4344754
OpenAlex
W1998055329
Cited by
124
References
15
Citations by year
2026: 6 · 2025: 13 · 2024: 10 · 2023: 5 · 2022: 7 · 2021: 14 · 2020: 11 · 2019: 12 · 2018: 15 · 2017: 16 · 2016: 10 · 2015: 5
FWCI
14.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship@McGill (McGill) (submittedVersion)
Funders
  • McGill University
  • Ministère du Développement Économique, de l’Innovation et de l’Exportation
  • Alzheimer's Society
  • Canadian Institutes of Health Research (MOP#119425, 119425, MOP133611, CIHR MOP 119425)
  • Natural Sciences and Engineering Research Council of Canada
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
docosahexaenoic acid, microglial activation, dendritic spine morphology, neuroinflammation, lipopolysaccharide, omega-3 polyunsaturated fatty acids, hippocampal CA1, synaptic transmission, nitric oxide, lipid droplets, mitochondrial function, neuron-glia interactions, neuroprotection
MeSH terms
Perilipin-2, Action Potentials, Animals, Animals, Newborn, Benzimidazoles, Carbocyanines, Cells, Cultured, Docosahexaenoic Acids, Gene Expression Regulation, Hippocampus, Membrane Proteins, Mice, Transgenic, Neurons, Nitric Oxide, Organ Culture Techniques, Polysaccharides, Microglia, Cytochromes c, Dendritic Spines, Mice, Lipid Droplets, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review