Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease

Authors: Minsook Ye, Hwan-Suck Chung, Chanju Lee, Moon Sik Yoon, A. Ram Yu, Jin Su Kim, Deok-Sang Hwang, Insop Shim, Hyunsu Bae

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

Alzheimer’s disease (AD) is a severe neuroinflammatory disease. CD4+Foxp3+ regulatory T cells (Tregs) modulate various inflammatory diseases via suppressing Th cell activation. There are increasing evidences that Tregs have beneficial roles in neurodegenerative diseases. Previously, we found the population of Treg cells was significantly increased by bee venom phospholipase A2 (bvPLA2) treatment in vivo and in vitro.

Methods

To examine the effects of bvPLA2 on AD, bvPLA2 was administered to 3xTg-AD mice, mouse model of Alzheimer’s disease. The levels of amyloid beta (Aβ) deposits in the hippocampus, glucose metabolism in the brain, microglia activation, and CD4+ T cell infiltration were analyzed to evaluate the neuroprotective effect of bvPLA2.

Results

bvPLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) positron emission tomography (PET). The levels of Aβ deposits in the hippocampus were dramatically decreased by bvPLA2 treatment. This neuroprotective effect of bvPLA2 was associated with microglial deactivation and reduction in CD4+ T cell infiltration. Interestingly, the neuroprotective effects of bvPLA2 were abolished in Treg-depleted mice.

Conclusions

The present studies strongly suggest that the increase of Treg population by bvPLA2 treatment might inhibit progression of AD in the 3xTg AD mice.

Literature
  1. Finder VH. Alzheimer's disease: a general introduction and pathomechanism. J Alzheimers Dis. 2010;22 Suppl 3:5–19.PubMed
  2. Honjo K, Black SE, Verhoeff NP. Alzheimer’s disease, cerebrovascular disease, and the beta-amyloid cascade. Can J Neurol Sci. 2012;39:712–28.PubMedView Article
  3. Kim DKSJ, Park JD, Choi BS. Copper induces the accumulation of amyloid-beta in the brain. Mol Cell Toxicol. 2013;9:57–66.View Article
  4. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430:631–9.PubMedPubMed CentralView Article
  5. Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol. 2006;6:404–16.PubMedView Article
  6. McGeer EG, McGeer PL. Inflammatory processes in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:741–9.PubMedView Article
  7. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358:461–7.PubMedView Article
  8. Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology. 2009;72:56–62.PubMedPubMed CentralView Article
  9. Rogers J, Lue LF. Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer’s disease. Neurochem Int. 2001;39:333–40.PubMedView Article
  10. Cheng D, Spiro AS, Jenner AM, Garner B, Karl T. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014.
  11. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–34.PubMedPubMed CentralView Article
  12. Terry Jr AV, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306:821–7.PubMedView Article
  13. Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther. 2009;1:7.PubMedPubMed CentralView Article
  14. Sabbagh MN. Drug development for Alzheimer’s disease: where are we now and where are we headed? Am J Geriatr Pharmacother. 2009;7:167–85.PubMedPubMed CentralView Article
  15. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–21.PubMedView Article
  16. Gimenez-Llort L, Blazquez G, Canete T, Johansson B, Oddo S, Tobena A, et al. Modeling behavioral and neuronal symptoms of Alzheimer’s disease in mice: a role for intraneuronal amyloid. Neurosci Biobehav Rev. 2007;31:125–47.PubMedView Article
  17. Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, et al. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem. 2006;281:1599–604.PubMedView Article
  18. Habermann E. Bee and wasp venoms. Science. 1972;177:314–22.PubMedView Article
  19. Linderoth L, Peters GH, Jorgensen K, Madsen R, Andresen TL. Synthesis of sn-1 functionalized phospholipids as substrates for secretory phospholipase A2. Chem Phys Lipids. 2007;146:54–66.PubMedView Article
  20. Dennis EA. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem. 1994;269:13057–60.PubMed
  21. Mukherjee AB, Miele L, Pattabiraman N. Phospholipase A2 enzymes: regulation and physiological role. Biochem Pharmacol. 1994;48:1–10.PubMedView Article
  22. Dennis EA, Rhee SG, Billah MM, Hannun YA. Role of phospholipase in generating lipid second messengers in signal transduction. FASEB J. 1991;5:2068–77.PubMed
  23. Granata F, Frattini A, Loffredo S, Del Prete A, Sozzani S, Marone G, et al. Signaling events involved in cytokine and chemokine production induced by secretory phospholipase A2 in human lung macrophages. Eur J Immunol. 2006;36:1938–50.PubMedView Article
  24. Kim H, Keum DJ, Kwak J, Chung HS, Bae H. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice. PLoS One. 2014;9:e114726.PubMedPubMed CentralView Article
  25. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11:47–60.PubMedView Article
  26. Ye M, Lee SG, Chung ES, Lim SJ, Kim WS, Yoon H, et al. Neuroprotective effects of cuscutae semen in a mouse model of Parkinson's disease. Evid Based Complement Alternat Med. 2014;2014:150153.PubMedPubMed Central
  27. Sala C, Rudolph-Correia S, Sheng M. Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. J Neurosci. 2000;20:3529–36.PubMed
  28. Paxinos G, Watson C, Pennisi M, Topple A. Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods. 1985;13:139–43.PubMedView Article
  29. Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, et al. Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med. 2006;47:999–1006.PubMed
  30. Bao Q, Newport D, Chen M, Stout DB, Chatziioannou AF. Performance evaluation of the inveon dedicated PET preclinical tomograph based on the NEMA NU-4 standards. J Nucl Med. 2009;50:401–8.PubMedPubMed CentralView Article
  31. Swartzwelder HS, Dyer RS, Holahan W, Myers RD. Activity changes in rats following acute trimethyltin exposure. Neurotoxicology. 1981;2:589–93.PubMed
  32. Setiady YY, Coccia JA, Park PU. In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcgammaRIII+ phagocytes. Eur J Immunol. 2010;40:780–786.PubMedView Article
  33. Lee H, Kwon Y, Lee JH, Kim J, Shin MK, Kim SH, Bae H: Methyl gallate exhibits potent antitumor activities by inhibiting tumor infiltration of CD4+CD25+ regulatory T cells. J Immunol. 2010;185:6698–705.PubMedView Article
  34. Karantzoulis S, Galvin JE. Distinguishing Alzheimer’s disease from other major forms of dementia. Expert Rev Neurother. 2011;11:1579–91.PubMedPubMed CentralView Article
  35. Schmole AC, Lundt R, Ternes S, Albayram O, Ulas T, Schultze JL, et al. Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer’s disease mouse model. Neurobiol Aging. 2015;36:710–9.PubMedView Article
  36. Solito E, Sastre M. Microglia function in Alzheimer’s disease. Front Pharmacol. 2012;3:14.PubMedPubMed CentralView Article
  37. Kadiu I, Glanzer JG, Kipnis J, Gendelman HE, Thomas MP. Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases. Neurotox Res. 2005;8:25–50.PubMedView Article
  38. McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev. 1995;21:195–218.PubMedView Article
  39. Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest. 2004;114:1209–17.PubMedPubMed CentralView Article
  40. Kuniyasu Y, Takahashi T, Itoh M, Shimizu J, Toda G, Sakaguchi S. Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000;12:1145–55.PubMedView Article
  41. Wang L, Xie Y, Zhu LJ, Chang TT, Mao YQ, Li J. An association between immunosenescence and CD4(+)CD25(+) regulatory T cells: a systematic review. Biomed Environ Sci. 2010;23:327–32.PubMedView Article
  42. Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76:77–98.PubMedView Article
  43. Jana M, Palencia CA, Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer’s disease. J Immunol. 2008;181:7254–62.PubMedPubMed CentralView Article
  44. Muehlhauser F, Liebl U, Kuehl S, Walter S, Bertsch T, Fassbender K. Aggregation-dependent interaction of the Alzheimer’s beta-amyloid and microglia. Clin Chem Lab Med. 2001;39:313–6.PubMedView Article
  45. Delgado S, Sheremata WA. The role of CD4+ T-cells in the development of MS. Neurol Res. 2006;28:245–9.PubMedView Article
  46. Town T, Tan J, Flavell RA, Mullan M. T-cells in Alzheimer’s disease. Neuromolecular Med. 2005;7:255–64.PubMedView Article
  47. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.PubMedView Article
  48. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.PubMedView Article
  49. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9.PubMedView Article
  50. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol. 2007;82:1083–94.PubMedView Article
  51. Subramanian S, Ayala P, Wadsworth TL, Harris CJ, Vandenbark AA, Quinn JF, Offner H. CCR6: a biomarker for Alzheimer’s-like disease in a triple transgenic mouse model. J Alzheimers Dis. 2010;22:619–29.PubMedPubMed Central
  52. Larbi A, Pawelec G, Witkowski JM, Schipper HM, Derhovanessian E, Goldeck D, et al. Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer’s disease. J Alzheimers Dis. 2009;17:91–103.PubMed
  53. Kim H, Lee H, Lee G, Jang H, Kim SS, Yoon H, et al. Phospholipase A2 inhibits cisplatin-induced acute kidney injury by modulating regulatory T cells by the CD206 mannose receptor. Kidney Int. 2015;88:550–9.PubMedView Article
  54. Klingenberg R, Gerdes N, Badeau RM, Gistera A, Strodthoff D, Ketelhuth DF, et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013;123:1323–34.PubMedPubMed CentralView Article
  55. Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007;204:57–63.PubMedPubMed CentralView Article
  56. Taguchi O, Takahashi T. Administration of anti-interleukin-2 receptor alpha antibody in vivo induces localized autoimmune disease. Eur J Immunol. 1996;26:1608–12.PubMedView Article
  57. McHugh RS, Shevach EM. Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol. 2002;168:5979–83.PubMedView Article
  58. Weitz TM, Gate D, Rezai-Zadeh K, Town T. MyD88 is dispensable for cerebral amyloidosis and neuroinflammation in APP/PS1 transgenic mice. Am J Pathol. 2014;184:2855–61.PubMedPubMed CentralView Article
  59. Goni F, Herline K, Peyser D, Wong K, Ji Y, Sun Y, et al. Immunomodulation targeting of both Abeta and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models. J Neuroinflammation. 2013;10:150.PubMedPubMed CentralView Article
  60. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging. 2003;24:1063–70.PubMedView Article
  61. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron. 2005;45:675–88.PubMedView Article
  62. Sperling RA, Dickerson BC, Pihlajamaki M, Vannini P, LaViolette PS, Vitolo OV, et al. Functional alterations in memory networks in early Alzheimer’s disease. Neuromolecular Med. 2010;12:27–43.PubMedPubMed CentralView Article
  63. Mirrione MM, Schiffer WK, Fowler JS, Alexoff DL, Dewey SL, Tsirka SE. A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. Neuroimage. 2007;38:34–42.PubMedPubMed CentralView Article
  64. Mirrione MM, Schiffer WK, Siddiq M, Dewey SL, Tsirka SE. PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy. Synapse. 2006;59:119–21.PubMedView Article
  65. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug Saf. 1998;19:465–80.PubMedView Article
Metadata
Title
Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease
Authors
Minsook Ye
Hwan-Suck Chung
Chanju Lee
Moon Sik Yoon
A. Ram Yu
Jin Su Kim
Deok-Sang Hwang
Insop Shim
Hyunsu Bae
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0476-z

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: implications in HIV-associated neurotoxicity

Research

Acute versus chronic phase mechanisms in a rat model of CRPS

Research

Cell cycle inhibition reduces inflammatory responses, neuronal loss, and cognitive deficits induced by hypobaria exposure following traumatic brain injury

Review

Multiple organ dysfunction and systemic inflammation after spinal cord injury: a complex relationship

Research

Brain radiation injury leads to a dose- and time-dependent recruitment of peripheral myeloid cells that depends on CCR2 signaling

Erratum

Erratum to: Exacerbation of blast-induced ocular trauma by an immune response