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Relationship Between Obesity, Alzheimer’s Disease, and Parkinson’s Disease: an Astrocentric View

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Abstract

Obesity is considered one of the greatest risk to human health and is associated with several factors including genetic components, diet, and physical inactivity. Recently, the relationship between obesity and numerous progressive and aging-related neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) have been observed. Thus, the involvement of the most abundant and heterogeneous group of glial cells in neurodegenerative diseases, the astrocytes, is caused by a combination of the failure on their normal homeostatic functions and the increase of toxic metabolites upon pathological event. Upon brain damage, molecular signals induce astrocyte activation and migration to the site of injury, entering in a highly active state, with the aim to contribute to ameliorating or worsening the pathology. In this regard, the aim of this review is to elucidate the relationship between obesity, Alzheimer’s disease, and Parkinson’s disease and highlight the role of astrocytes in these pathologies.

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References

  1. Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13(4):3391–3396. doi:10.3892/mmr.2016.4948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ashrafian H, Harling L, Darzi A, Athanasiou T (2013) Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions? Metab Brain Dis. doi:10.1007/s11011-013-9412-4

    PubMed  Google Scholar 

  3. Mattson MP, Pedersen WA, Duan W, Culmsee C, Camandola S (1999) Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 893(1):154–175. doi:10.1111/j.1749-6632.1999.tb07824.x

    Article  CAS  PubMed  Google Scholar 

  4. Perl DP, Olanow CW, Calne D (1998) Alzheimer’s disease and Parkinson’s disease: distinct entities or extremes of a spectrum of neurodegeneration? Ann Neurol 44(3 Suppl 1):S19–S31. doi:10.1002/ana.410440705

    Article  CAS  PubMed  Google Scholar 

  5. World Health Organization (WHO) (2011) World health statistics 2011. WHO Press, Geneva, p. 162

    Google Scholar 

  6. World Health Organization (WHO) (2010) World health statistics 2010. WHO Press, Geneva, p. 168

    Google Scholar 

  7. Caveney E, Caveney BJ, Somaratne R, Turner JR, Gourgiotis L (2011) Pharmaceutical interventions for obesity: a public health perspective. doi:10.1111/j.1463-1326.2010.01353.x

  8. Aitlhadj L, Ávila DS, Benedetto A, Aschner M, Stürzenbaum SR (2011) Environmental exposure, obesity, and Parkinson’s disease: lessons from fat and old worms. Environ Health Perspect. doi:10.1289/ehp.1002522

    PubMed  Google Scholar 

  9. Mardinoglu A, Kampf C, Asplund A, Fagerberg L, Hallström BM, Edlund K, Blüher M, Pontén F et al (2014) Defining the human adipose tissue proteome to reveal metabolic alterations in obesity. J Proteome Res 13(11):5106–5119. doi:10.1021/pr500586e

    Article  CAS  PubMed  Google Scholar 

  10. Wolozin B (2004) Cholesterol and the biology of Alzheimer’s disease. Neuron 41(1):7–10. doi:10.1016/s0896-6273(03)00840-7

    Article  CAS  PubMed  Google Scholar 

  11. Profenno LA, Porsteinsson AP, Faraone SV (2010) Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 67:505–512. doi:10.1016/j.biopsych.2009.02.013

    Article  PubMed  Google Scholar 

  12. Naderali EK, Ratcliffe SH, Dale MC (2009) Obesity and Alzheimer’s disease: a link between body weight and cognitive function in old age. Am J Alzheimer’s Dis Other Demen 24(6):445–449. doi:10.1177/1533317509348208

    Article  Google Scholar 

  13. Ford JH (2010) Saturated fatty acid metabolism is key link between cell division, cancer, and senescence in cellular and whole organism aging. Age. doi:10.1007/s11357-009-9128-x

    PubMed  PubMed Central  Google Scholar 

  14. Liu L, Zhang K, Sandoval H, Yamamoto S, Jaiswal M, Sanz E, Li Z, Hui J et al (2015) Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 160:177–190. doi:10.1016/j.cell.2014.12.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barreto G, White RE, Ouyang Y, Xu L, Giffard RG (2011) Astrocytes: targets for neuroprotection in stroke. Cent Nerv Syst Agents Med Chem 11(2):164–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. G. E. Barreto, J. Gonzalez, F. Capani and L. Morales: Role of astrocytes in neurodegenerative diseases. Neurodegenerative Dis ProcessPrevent Protect Monit 257–272 (2011)

  17. Barreto GE, Gonzalez J, Torres Y, Morales L (2011) Astrocytic-neuronal crosstalk: implications for neuroprotection from brain injury. Neurosci Res 71(2):107–113. doi:10.1016/j.neures.2011.06.004

    Article  PubMed  Google Scholar 

  18. Barreto GE, Sun X, Xu L, Giffard RG (2011) Astrocyte proliferation following stroke in the mouse depends on distance from the infarct. PLoS One 6(11):e27881. doi:10.1371/journal.pone.0027881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Logica T, Riviere S, Holubiec MI, Castilla R, Barreto GE, Capani F (2016) Metabolic changes following perinatal asphyxia: role of astrocytes and their interaction with neurons. Front Aging Neurosci 8:116. doi:10.3389/fnagi.2016.00116

    Article  PubMed  PubMed Central  Google Scholar 

  20. Acaz-Fonseca E, Avila-Rodriguez M, Garcia-Segura LM, Barreto GE (2016) Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions. Prog Neurobiol. doi:10.1016/j.pneurobio.2016.06.002

    PubMed  Google Scholar 

  21. Iglesias J, Morales L, Barreto GE (2016) Metabolic and inflammatory adaptation of reactive astrocytes: role of PPARs. Mol Neurobiol. doi:10.1007/s12035-016-9833-2

    PubMed  Google Scholar 

  22. Garzon D, Cabezas R, Vega N, Avila-Rodriguez M, Gonzalez J, Gomez RM, Echeverria V, Aliev G et al (2016) Novel approaches in astrocyte protection: from experimental methods to computational approaches. J Mol Neurosci 58(4):483–492. doi:10.1007/s12031-016-0719-6

    Article  CAS  PubMed  Google Scholar 

  23. Cabezas R, Avila-Rodriguez M, Vega-Vela NE, Echeverria V, Gonzalez J, Hidalgo OA, Santos AB, Aliev G et al (2016) Growth factors and astrocytes metabolism: possible roles for platelet derived growth factor. Med Chem 12(3):204–210

    Article  CAS  PubMed  Google Scholar 

  24. Cabezas R, Avila M, Gonzalez J, El-Bacha RS, Baez E, Garcia-Segura LM, Jurado Coronel JC, Capani F et al (2014) Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front Cell Neurosci 8:211. doi:10.3389/fncel.2014.00211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Romero J, Muniz J, Logica Tornatore T, Holubiec M, Gonzalez J, Barreto GE, Guelman L, Lillig CH et al (2014) Dual role of astrocytes in perinatal asphyxia injury and neuroprotection. Neurosci Lett 565:42–46. doi:10.1016/j.neulet.2013.10.046

    Article  CAS  PubMed  Google Scholar 

  26. Barreto GE, White RE, Xu L, Palm CJ, Giffard RG (2012) Effects of heat shock protein 72 (Hsp72) on evolution of astrocyte activation following stroke in the mouse. Exp Neurol 238(2):284–296. doi:10.1016/j.expneurol.2012.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cabezas R, El-Bacha RS, Gonzalez J, Barreto GE (2012) Mitochondrial functions in astrocytes: neuroprotective implications from oxidative damage by rotenone. Neurosci Res 74(2):80–90. doi:10.1016/j.neures.2012.07.008

    Article  CAS  PubMed  Google Scholar 

  28. Guillamón-Vivancos T, Gómez-Pinedo U, Matías-Guiu J (2013) Astrocytes in neurodegenerative diseases (I): function and molecular description. Neurologia (Barcelona, Spain) 30:1–11. doi:10.1016/j.nrl.2012.12.007

    Google Scholar 

  29. Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett. doi:10.1016/j.neulet.2013.12.071

    PubMed  Google Scholar 

  30. Huang S, Rutkowsky JM, Snodgrass RG, Ono-Moore KD, Schneider DA, Newman JW, Adams SH, Hwang DH (2012) Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways. J Lipid Res 53:2002–2013. doi:10.1194/jlr.D029546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu C-C, Liu C-C, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2):106–118. doi:10.1038/nrneurol.2012.263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ajuwon KM, Spurlock ME (2005) Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3 T3-L1 adipocytes. J Nutr 135:1841–1846

    CAS  PubMed  Google Scholar 

  33. Boden G (2008) Obesity and free fatty acids. Endocrinol Metab Clin N Am. doi:10.1016/j.ecl.2008.06.007

    Google Scholar 

  34. Scheller JR, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta-Mol Cell Res 1813:878–888. doi:10.1016/j.bbamcr.2011.01.034

    Article  CAS  Google Scholar 

  35. Xanthos DN, Sandkühler J (2014) Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15:43–53. doi:10.1038/nrn3617

    Article  CAS  PubMed  Google Scholar 

  36. Ben Haim L, Carrillo-de Sauvage M-A, Ceyzériat K, Escartin C (2015) Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 9:278. doi:10.3389/fncel.2015.00278

    Article  PubMed  PubMed Central  Google Scholar 

  37. Buckman LB, Hasty AH, Flaherty DK, Buckman CT, Thompson MM, Matlock BK, Weller K, Ellacott KLJ (2014) Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun 35:33–42. doi:10.1016/j.bbi.2013.06.007

    Article  CAS  PubMed  Google Scholar 

  38. Whitmer RA (2007) The epidemiology of adiposity and dementia. Curr Alzheimer Res 4:117–122. doi:10.2174/156720507780362065

    Article  CAS  PubMed  Google Scholar 

  39. Bruce-Keller AJ, Keller JN, Morrison CD (2009) Obesity and vulnerability of the CNS. Biochim Biophys Acta Mol basis Dis. doi:10.1016/j.bbadis.2008.10.004

    Google Scholar 

  40. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867. doi:10.1038/nature05485

    Article  CAS  PubMed  Google Scholar 

  41. Awada R, Parimisetty A, DHellencourt C (2008) Influence of obesity on neurodegenerative diseases. Obésité 3:27–32. doi:10.1007/s11690-008-0100-1

    Article  Google Scholar 

  42. Mathis D (2013) Immunological goings-on in visceral adipose tisuue. Cell Metab 17:851–859. doi:10.1016/j.cmet.2013.05.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Furuhashi M, Fucho R, Görgün CZ, Tuncman G, Cao H, Hotamisligil GS (2008) Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Investig 118:2640–2650. doi:10.1172/JC134750

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–S268. doi:10.2337/dc08-s264

    Article  CAS  PubMed  Google Scholar 

  45. García-Cáceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, Jastroch M, Johansson P et al (2016) Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166(4):867–880. doi:10.1016/j.cell.2016.07.028

    Article  PubMed  CAS  Google Scholar 

  46. Tomas E, Lin Y-S, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman N (2002) Hyperglycemia and insulin resistance: possible mechanisms. Ann N Y Acad Sci 967:43–51. doi:10.1111/j.1749-6632.2002.tb04262.x

    Article  CAS  PubMed  Google Scholar 

  47. Dixit V, Weeraratna A, Hyunwon Y, Bertak D, Jenkins A, Riggins G, Eberhart C, Taub D (2006) Ghrelin and the growth hormone Secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J Biol Chem 281(24):16681–16690. doi:10.1021/jp809000e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hsuchou H, He Y, Kastin AJ, Tu H, Markadakis EN, Rogers RC, Fossier PB, Pan W (2009) Obesity induces functional astrocytic leptin receptors in hypothalamus. Brain 132:889–902. doi:10.1093/brain/awp029

    Article  PubMed  PubMed Central  Google Scholar 

  49. Heni M, Hennige AM, Peter A, Siegel-Axel D, Ordelheide AM, Krebs N, Machicao F, Fritsche A et al (2011) Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS One 6:e21594. doi:10.1371/journal.pone.0021594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brown LM, Gent L, Davis K, Clegg DJ (2010) Metabolic impact of sex hormones on obesity. Brain Res 1350:77–85. doi:10.1016/j.brainres.2010.04.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rasmussen MH (2010) Obesity, growth hormone and weight loss. Mol Cell Endocrinol 316:147–153. doi:10.1016/j.mce.2009.08.017

    Article  CAS  PubMed  Google Scholar 

  52. Kim JG, Suyama S, Koch M, Jin S, Argente-arizon P, Gao Y, Garcia-Caceres C et al (2014) Leptin signaling in GFAP-expressing adult glia cells regulates hypothalamic neuronal circuits and feeding. Nat Neurosci 17(7):908–910. doi:10.1038/nn.3725.Leptin

    Article  CAS  PubMed  Google Scholar 

  53. Wang Y, Hsuchou H, He Y, Kastin A, Pan W (2015) Role of astrocytes in leptin signaling. J Mol Neurosci 56:829–839. doi:10.1007/s12031-015-0518-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Garwood CJ, Ratcliffe LE, Morgan SV, Simpson JE, Owens H, Vazquez-Villaseñor I, Heath PR, Romero IA et al (2015) Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol Brain 8:51. doi:10.1186/s13041-015-0138-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W et al (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122–2125

    Article  CAS  PubMed  Google Scholar 

  56. Havrankova J, Roth J, Brownstein M (1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature. doi:10.1038/272827a0

    PubMed  Google Scholar 

  57. Figlewicz DP, Szot P, Chavez M, Woods SC, Veith RC (1994) Intraventricular insulin increases dopamine transporter mRNA in rat VTA/substantia nigra. Brain Res 644:331–334. doi:10.1016/0006-8993(94)91698-5

    Article  CAS  PubMed  Google Scholar 

  58. Phatnani H, Maniatis T (2015) Astrocytes in neurodegenerative disease. Cold Spring Harb Perspect Biol 7(6):a020628–a020628. doi:10.1101/cshperspect.a020628

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. A. S. Association: In Alzheimer´s Association (2016) http://www.alz.org/

  60. Hebert L, Weuve J, Scherr P, Evans D (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80(19):1778–1783. doi:10.1212/WNL.0b013e31828726f5

    Article  PubMed  PubMed Central  Google Scholar 

  61. Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2(12):679–689. doi:10.1038/ncpneuro0355

    Article  CAS  PubMed  Google Scholar 

  62. Selkoe DJ (2000) The genetics and molecular pathology of Alzheimer’s disease—roles of amyloid and the presenilins. Neurol Clin 18(4):903

    Article  CAS  PubMed  Google Scholar 

  63. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031. doi:10.1016/S0140-6736(10)61349-9

    Article  PubMed  Google Scholar 

  64. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science (New York, NY) 297(5580):353–356. doi:10.1126/science.1072994

    Article  CAS  Google Scholar 

  65. Small SA, Duff K (2008) Linking aβ and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron. doi:10.1016/j.neuron.2008.11.007

    Google Scholar 

  66. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron. doi:10.1016/j.neuron.2004.09.010

    Google Scholar 

  67. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M et al (2010) Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A 107(15):7036–7041. doi:10.1073/pnas.1000645107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gustafson D (2006) Adiposity indices and dementia. Lancet Neurol 5(8):713–720. doi:10.1016/S1474-4422(06)70526-9

    Article  PubMed  Google Scholar 

  69. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K (2008) Central obesity and increased risk of dementia more than three decades later. Neurology 71(14):1057–1064. doi:10.1212/01.wnl.0000306313.89165.ef

    Article  CAS  PubMed  Google Scholar 

  70. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I (2003) An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 163(13):1524–1528. doi:10.1001/archinte.163.13.1524

    Article  PubMed  Google Scholar 

  71. Chibber S, Alexiou A, Alama MN, Barreto GE, Aliev G, Ashraf GM (2016) A synopsis on the linkage between age-related dementias and vascular disorders. CNS Neurol Disord Drug Targets 15(2):250–258

    Article  CAS  PubMed  Google Scholar 

  72. Gonzalez-Reyes RE, Aliev G, Avila-Rodrigues M, Barreto GE (2016) Alterations in glucose metabolism on cognition: a possible link between diabetes and dementia. Curr Pharm Des 22(7):812–818

    Article  CAS  PubMed  Google Scholar 

  73. Blach-Olszewska Z, Zaczynska E, Gustaw-Rothenberg K, Avila-Rodrigues M, Barreto GE, Leszek J, Aliev G (2015) The innate immunity in Alzheimer disease- relevance to pathogenesis and therapy. Curr Pharm Des 21(25):3582–3588

    Article  CAS  PubMed  Google Scholar 

  74. Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ (2012) AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging 33:1400–1410. doi:10.1016/j.neurobiolaging.2011.02.003

    Article  PubMed  CAS  Google Scholar 

  75. Milionis HJ, Florentin M, Giannopoulos S (2008) Metabolic syndrome and Alzheimer’s disease: a link to a vascular hypothesis? CNS Spectrums 13(7):606–613

    Article  PubMed  Google Scholar 

  76. Razay G, Wilcock GK (1994) Hyperinsulinaemia and alzheimer’s disease. Age Ageing 23(5):396–399. doi:10.1093/ageing/23.5.396

    Article  CAS  PubMed  Google Scholar 

  77. Di Paolo G, Kim T-W (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12(5):284–296. doi:10.1038/nrn3012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cattin L, Bordin P, Fonda M, Adamo C, Barbone F, Bovenzi M, Manto A, Pedone C et al (1997) Factors associated with cognitive impairment among older Italian inpatients. Gruppo Italiano di Farmacovigilanza nell’Anziano (G.I.F.A.). J Am Geriatr Soc 45:1324–1330. doi:10.1111/j.1532-5415.1997.tb02931.x

    Article  CAS  PubMed  Google Scholar 

  79. Cournot M, Marquié JC, Ansiau D, Martinaud C, Fonds H, Ferrières J, Ruidavets JB (2006) Relation between body mass index and cognitive function in healthy middle-aged men and women. Neurology 67:1208–1214. doi:10.1212/01.wnl.0000238082.13860.50

    Article  CAS  PubMed  Google Scholar 

  80. Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB (2005) Obesity, diabetes and cognitive deficit: the Framingham heart study. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2005.08.019

    PubMed  Google Scholar 

  81. Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB (2003) Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord: J Int Assoc Study Obes 27:260–268. doi:10.1038/sj.ijo.802225

    Article  CAS  Google Scholar 

  82. Gunstad J, Paul RH, Cohen RA, Tate DF, Spitznagel MB, Gordon E (2007) Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr Psychiatry 48:57–61. doi:10.1016/j.comppsych.2006.05.001

    Article  PubMed  Google Scholar 

  83. Sabia SV, Kivimaki M, Shipley MJ, Marmot MG, Singh-Manoux A (2009) Body mass index over the adult life course and cognition in late midlife: the Whitehall II Cohort Study. Am J Clin Nutr 89:601–607. doi:10.3945/ajcn.2008.26482

    Article  CAS  PubMed  Google Scholar 

  84. Enzinger C, Fazekas F, Matthews PM, Ropele S, Schmidt H, Smith S, Schmidt R (2005) Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects. Neurology 64:1704–1711. doi:10.1212/01.WNL.0000161871.83614.BB

    Article  CAS  PubMed  Google Scholar 

  85. Liang X, Wang Q, Hand T, Wu L, Breyer RM, Montine TJ, Andreasson K (2005) Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer’s disease. J Neurosci: Off J Soc Neurosci 25(44):10180–10187. doi:10.1523/JNEUROSCI.3591-05.2005

    Article  CAS  Google Scholar 

  86. Taki Y, Kinomura S, Sato K, Inoue K, Goto R, Okada K, Uchida S, Kawashima R et al (2008) Relationship between body mass index and gray matter volume in 1,428 healthy individuals. Obesity (Silver Spring, MD) 16:119–124. doi:10.1038/oby.2007.4

    Article  Google Scholar 

  87. Lynch CM, Kinzenbaw DA, Chen X, Zhan S, Mezzetti E, Filosa J, Ergul A, Faulkner JL et al (2013) Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity. Stroke 44:3195–3201. doi:10.1161/STROKEAHA.113.001366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-Pinilla F (2002) A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112:803–814. doi:10.1016/S0306-4522(02)00123-9

    Article  CAS  PubMed  Google Scholar 

  89. Julien C, Tremblay C, Phivilay A, Berthiaume L, Emond V, Julien P, Calon FDR (2010) High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging 31:1516–1531. doi:10.1016/j.neurobiolaging.2008.08.022

    Article  CAS  PubMed  Google Scholar 

  90. Leboucher A, Laurent C, Fernandez F, Burnouf S, Troquier L, Eddarkaoui S, Demeyer D, Caillierez R et al (2013) Detrimental effects of diet-induced obesity on tau pathology are independent of insulin resistance in tau transgenic mice. Diabetes. doi:10.2337/db12-0866

    PubMed  PubMed Central  Google Scholar 

  91. Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32. doi:10.1016/j.jneuroim.2009.11.010

    Article  CAS  PubMed  Google Scholar 

  92. Puig KL, Floden AM, Adhikari R, Golovko MY, Combs CK (2012) Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS One 7:e0030378. doi:10.1371/journal.pone.0030378

    Article  CAS  Google Scholar 

  93. Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR (2008) High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem 106:475–485. doi:10.1111/j.1471-4159.2008.05415.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mrak RE (2009) Alzheimer-type neuropathological changes in morbidly obese elderly individuals. Clin Neuropathol 28:40–45

    Article  CAS  PubMed  Google Scholar 

  95. Gunstad J, Lhotsky A, Wendell CR, Ferrucci L, Zonderman AB (2010) Longitudinal examination of obesity and cognitive function: results from the Baltimore longitudinal study of aging. Neuroepidemiology 34:222–229. doi:10.1159/000297742

    Article  PubMed  PubMed Central  Google Scholar 

  96. Liang J, Matheson BE, Kaye WH, Boutelle KN (2014) Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents. Int J Obes 38:494–506. doi:10.1038/ijo.2013.142

    Article  CAS  Google Scholar 

  97. Morales-Briceño HA, Cervantes-Arriaga AB, Rodríguez-Violante MAB, Calleja-Castillo JB, Corona TB (2012) Overweight is more prevalent in patients with parkinson’s disease [Excesso de peso é mais frequente em pacientes com doença de Parkinson]. Arq Neuropsiquiatr 70:843–846. doi:10.1590/S0004-282X2012001100004

    Article  PubMed  Google Scholar 

  98. Rivera P, Pérez-Martín M, Pavón FJ, Serrano A, Crespillo A, Cifuentes M, López-Ávalos MD, Grondona JM et al (2013) Pharmacological Administration of the Isoflavone Daidzein Enhances Cell Proliferation and Reduces High Fat Diet-Induced Apoptosis and gliosis in the rat hippocampus. PLoS One 8:e0064750. doi:10.1371/journal.pone.0064750

    Google Scholar 

  99. Li W, Prakash R, Chawla D, Du W, Didion SP, Filosa JA, Zhang Q, Brann DW et al (2013) Early effects of high-fat diet on neurovascular function and focal ischemic brain injury. Am J Physiol Regul Integr Comp Physiol 304:R1001–R1008. doi:10.1152/ajpregu.00523.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pepping JK, Freeman LR, Gupta S, Keller JN, Bruce-Keller AJ (2013) NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet. Am J Physiol Endocrinol Metab 304:E392–E404. doi:10.1152/ajpendo.00398.2012

    Article  CAS  PubMed  Google Scholar 

  101. Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet. doi:10.1016/S0140-6736(09)60492-X

    Google Scholar 

  102. Jurado-Coronel JC, Avila-Rodriguez M, Echeverria V, Hidalgo OA, Gonzalez J, Aliev G, Barreto GE (2016) Implication of green tea as a possible therapeutic approach for Parkinson disease. CNS Neurol Disord Drug Targets 15(3):292–300

    Article  CAS  PubMed  Google Scholar 

  103. dos Santos AB, Kohlmeier KA, Barreto GE (2015) Are sleep disturbances preclinical markers of Parkinson’s disease? Neurochem Res 40(3):421–427. doi:10.1007/s11064-014-1488-7

    Article  CAS  PubMed  Google Scholar 

  104. Sutachan JJ, Casas Z, Albarracin SL, Stab BR 2nd, Samudio I, Gonzalez J, Morales L, Barreto GE (2012) Cellular and molecular mechanisms of antioxidants in Parkinson’s disease. Nutr Neurosci 15(3):120–126. doi:10.1179/1476830511Y.0000000033

    Article  CAS  PubMed  Google Scholar 

  105. Albarracin SL, Stab B, Casas Z, Sutachan JJ, Samudio I, Gonzalez J, Gonzalo L, Capani F et al (2012) Effects of natural antioxidants in neurodegenerative disease. Nutr Neurosci 15(1):1–9. doi:10.1179/1476830511Y.0000000028

    Article  CAS  PubMed  Google Scholar 

  106. Statistics on Parkinson’s (2016) Parkinson’s Disease Foundation, Inc. http://www.pdf.org/en/parkinson_statistics

  107. Braak H, Del Tredici K, Rüb U, De Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211. doi:10.1016/S0197-4580(02)00065-9

    Article  PubMed  Google Scholar 

  108. Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. doi:10.1111/j.1365-2990.2007.00874.x

    PubMed  Google Scholar 

  109. Nandhagopal R, Kuramoto L, Schulzer M, Mak E, Cragg J, Lee CS, McKenzie J, McCormick S et al (2009) Longitudinal progression of sporadic Parkinson’s disease: a multi-tracer positron emission tomography study. Brain 132(11):2970–2979. doi:10.1093/brain/awp209

    Article  CAS  PubMed  Google Scholar 

  110. Logroscino G, Marder K, Cote L, Tang MX, Shea S, Mayeux R (1996) Dietary lipids and antioxidants in Parkinson’s disease: a population-based, case-control study. Ann Neurol 39:89–94. doi:10.1002/ana.410390113

    Article  CAS  PubMed  Google Scholar 

  111. Hu G, Hu G, Pekkarinen H, Hänninen O, Tian H, Jin R (2002) Comparison of dietary and non-dietary risk factors in overweight and normal-weight Chinese adults. Br J Nutr 88:91–97. doi:10.1079/BJNBJN2002590

    Article  CAS  PubMed  Google Scholar 

  112. Hu G, Pekkarinen H, Hänninen O, Yu Z, Guo Z, Tian H (2002) Commuting, leisure-time physical activity, and cardiovascular risk factors in China. Med Sci Sports Exerc 34(2):234–238. doi:10.1097/00005768-200202000-00009

    Article  PubMed  Google Scholar 

  113. Chen H, Zhang SM, Schwarzschild MA, Hernán MA, Ascherio A (2005) Physical activity and the risk of Parkinson disease. Neurology 64(4):664–669. doi:10.1212/01.WNL.0000151960.28687.93

    Article  CAS  PubMed  Google Scholar 

  114. Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, Rossi-Fanelli F (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition (Burbank, Los Angeles County, Calif) 16(10):843–857

    Article  CAS  Google Scholar 

  115. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671. doi:10.1038/35007534

    CAS  PubMed  Google Scholar 

  116. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusll N, Fowler JS (2001) Brain dopamine and obesity. Lancet 357(9253):354–357. doi:10.1016/S0140-6736(00)03643-6

    Article  CAS  PubMed  Google Scholar 

  117. Langston J, Forno L (1978) The hypothalamus in Parkinson’s disease. Int J Neurosci 33(0020–7454):257–259

    Google Scholar 

  118. Shannak K, Rajput A, Rozdilsky B, Kish S, Gilbert J, Hornykiewicz O (1994) Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson’s disease and normal subjects. Brain Res 639(1):33–41

    Article  CAS  PubMed  Google Scholar 

  119. de Weijer BA, van de Giessen E, van Amelsvoort TA, Boot E, Braak B, Janssen IM, van de Laar A, Fliers E et al (2011) Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects. EJNMMI Res 1:37. doi:10.1186/2191-219X-1-37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Martel P, Fantino M (1996) Mesolimbic dopaminergic system activity as a function of food reward: a microdialysis study. Pharmacol Biochem Behav 53(1):221–226. doi:10.1016/0091-3057(95)00187-5

    Article  CAS  PubMed  Google Scholar 

  121. Abbott RD, Ross GW, White LR, Nelson JS, Masaki KH, Tanner CM, Curb JD, Blanchette PL et al (2002) Midlife adiposity and the future risk of Parkinson’s disease. Neurology 59:1051–1057. doi:10.1212/WNL.59.7.1051

    Article  CAS  PubMed  Google Scholar 

  122. Chen H, Zhang S, Schwarzschild M, Hernan M, Willett W, Ascherio A (2004) Obesity and the risk of Parkinson’s disease. Am J Epidemiol 159:547–555. doi:10.1093/aje/kwh059

    Article  PubMed  Google Scholar 

  123. Bachmann CG, Zapf A, Brunner E, Trenkwalder C (2009) Dopaminergic treatment is associated with decreased body weight in patients with Parkinson’s disease and dyskinesias. Eur J Neurol 16:895–901. doi:10.1111/j.1468-1331.2009.02617.x

    Article  CAS  PubMed  Google Scholar 

  124. Bousquet M, St-Amour I, Vandal M, Julien P, Cicchetti F, Calon F (2012) High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice. Neurobiol Dis 45:529–538. doi:10.1016/j.nbd.2011.09.009

    Article  CAS  PubMed  Google Scholar 

  125. Choi JY, Jang EH, Park CS, Kang JH (2005) Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic Biol Med 38:806–816. doi:10.1016/j.freeradbiomed.2004.12.008

    Article  CAS  PubMed  Google Scholar 

  126. Morris JK, Bomhoff GL, Stanford JA, Geiger PC (2010) Neurodegeneration in an animal model of Parkinson’s disease is exacerbated by a high-fat diet. Am J Physiol Regul Integr Comp Physiol 299:R1082–R1090. doi:10.1152/ajpregu.00449.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Driver J, Smith A, Buring J (2008) Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease. Diabetes 31:8–10. doi:10.2337/dc08-0688

    Google Scholar 

  128. Palacios N, Gao X, McCullough ML, Jacobs EJ, Patel AV, Mayo T, Schwarzschild MA, Ascherio A (2011) Obesity, diabetes, and risk of Parkinson’s disease. Mov Disord: Off J Mov Dis Soc 26:2253–2259. doi:10.1002/mds.23855

    Article  Google Scholar 

  129. Correale J, Villa A (2004) The neuroprotective role of inflammation in nervous system injuries. J Neurol 251:1304–1316. doi:10.1007/s00415-004-0649-z

    Article  PubMed  Google Scholar 

  130. Farooqui AA, Horrocks LA, Farooqui T (2007) Modulation of inflammation in brain: a matter of fat. J Neurochem 101:577–599. doi:10.1111/j.1471-4159.2006.04371.x

    Article  CAS  PubMed  Google Scholar 

  131. Echeverria V, Grizzell JA, Barreto GE (2016) Neuroinflammation: a therapeutic target of cotinine for the treatment of psychiatric disorders? Curr Pharm Des 22(10):1324–1333

    Article  CAS  PubMed  Google Scholar 

  132. Leszek J, Barreto GE, Gasiorowski K, Koutsouraki E, Avila-Rodrigues M, Aliev G (2016) Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS Neurol Disord Drug Targets 15(3):329–336

    Article  CAS  PubMed  Google Scholar 

  133. Carson MJ, Thrash JC, Walter B (2006) Survival. Clin Neurosci 6(5):237–245. doi:10.1016/j.cnr.2006.09.004.The

    Article  CAS  Google Scholar 

  134. Ransohoff RM, Schafer D, Vincent A, Blachère NE, Bar-Or A (2015) neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics 12:896–909. doi:10.1007/s13311-015-0385-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Adelson JD, Barreto GE, Xu L, Kim T, Brott BK, Ouyang YB, Naserke T, Djurisic M et al (2012) Neuroprotection from stroke in the absence of MHCI or PirB. Neuron 73(6):1100–1107. doi:10.1016/j.neuron.2012.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Streit WJ, Mrak RE, Griffin WST (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflam 1:–14. doi:10.1186/1742-2094-1-14

  137. Lo D, Feng L, Li L, Carson MJ, Crowley M, Pauza M, Nguyen A, Reilly CR (1999) Integrating innate and adaptive immunity in the whole animal. Immunol Rev 169:225–239. doi:10.1111/j.1600-065X.1999.tb01318.x

    Article  CAS  PubMed  Google Scholar 

  138. Amor S, Puentes F, Baker D, Van Der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology. doi:10.1111/j.1365-2567.2009.03225.x

    PubMed  PubMed Central  Google Scholar 

  139. Hein AM, O’Banion MK (2009) Neuroinflammation and memory: the role of prostaglandins. Mol Neurobiol. doi:10.1007/s12035-009-8066-z

    PubMed  PubMed Central  Google Scholar 

  140. Kohman RA, Rhodes JS (2013) Neurogenesis, inflammation and behavior. Brain Behav Immun 27:22–32. doi:10.1016/j.bbi.2012.09.003

    Article  CAS  PubMed  Google Scholar 

  141. Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA (2012) Neuroinflammation and synaptic loss. Neurochem Res. doi:10.1007/s11064-012-0708-2

    Google Scholar 

  142. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86:7611–7615. doi:10.1073/pnas.86.19.7611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Mayer CM, Belsham DD (2010) Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5′ monophosphate-activated protein kinase activation. Endocrinology 151:576–585. doi:10.1210/en.2009-1122

    Article  CAS  PubMed  Google Scholar 

  144. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. doi:10.1146/annurev-immunol-031210-101322

    Article  CAS  PubMed  Google Scholar 

  145. Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho DP, Carvalheira JB, Velloso LA (2011) Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology 152(4):1314–1326. doi:10.1210/en.2010-0659

    Article  CAS  PubMed  Google Scholar 

  146. Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, Romanatto T, Pascoal LB et al (2012) Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61(6):1455–1462. doi:10.2337/db11-0390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sartorius T, Lutz SZ, Hoene M, Waak J, Peter A, Weigert C, Rammensee HG, Kahle PJ et al (2012) Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture. FASEB J 26(5):1799–1809. doi:10.1096/fj.11-191023

    Article  CAS  PubMed  Google Scholar 

  148. Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG et al (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab 296:E1003–E1012. doi:10.1152/ajpendo.90377.2008

    Article  CAS  PubMed  Google Scholar 

  149. Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132:344–362. doi:10.1016/j.cell.2008.01.020

    Article  CAS  PubMed  Google Scholar 

  150. Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R et al (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10(4):249–259. doi:10.1016/j.cmet.2009.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Pellerin L, Magistretti PJ (2004) Neuroenergetics: calling upon astrocytes to satisfy hungry neurons. Neuroscientist: Rev J Bringing Neurobiol, Neurol Psychiatry 10:53–62. doi:10.1177/1073858403260159

    Article  CAS  Google Scholar 

  152. Ridet JL, Alonso G, Chauvet N, Chapron J, Koenig J, Privat A (1996) Immunocytochemical characterization of a new marker of fibrous and reactive astrocytes. Cell Tissue Res 283:39–49. doi:10.1007/s004410050510

    Article  CAS  PubMed  Google Scholar 

  153. Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, de Souza CT, Grimaldi R, Stahl M et al (2012) Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One 7(1):e30571. doi:10.1371/journal.pone.0030571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG, Ozcan U (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9(1):35–51. doi:10.1016/j.cmet.2008.12.004

    Article  CAS  PubMed  Google Scholar 

  155. Mazzanti M, Sul JY, Haydon PG (2001) Glutamate on demand: astrocytes as a ready source. Neuroscientist: Rev J Bringing Neurobiol, Neurol Psychiatry 7:396–405. doi:10.1177/107385840100700509

    Article  CAS  Google Scholar 

  156. Romanatto T, Roman EA, Arruda AP, Denis RG, Solon C, Milanski M, Moraes JC, Bonfleur ML et al (2009) Deletion of tumor necrosis factor-α receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. J Biol Chem 284:36213–36222. doi:10.1074/jbc.M109.030874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Pasti L (1997) A. Volterra, T. Pozzan and G. Carmignoto: intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci: Off J Soc Neurosci 17:7817–7830. doi:10.1038/nrn1722

    CAS  Google Scholar 

  158. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215. doi:10.1016/S0166-2236(98)01349-6

    Article  CAS  PubMed  Google Scholar 

  159. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1998) Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons. Eur J Neurosci 10:2129–2142. doi:10.1046/j.1460-9568.1998.00221.x

    Article  CAS  PubMed  Google Scholar 

  160. Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N, Chan S, Li C et al (2004) Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci U S A 101:8384–8389. doi:10.1073/pnas.0402140101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DML, Anhe G et al (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci: Off J Soc Neurosci 29:359–370. doi:10.1523/JNEUROSCI.2760-08.2009

    Article  CAS  Google Scholar 

  162. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJA, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146(10):4192–4199. doi:10.1210/en.2004-1520

    Article  CAS  PubMed  Google Scholar 

  163. Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA et al (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Investig 122(1):153–162. doi:10.1172/JCI59660

    Article  CAS  PubMed  Google Scholar 

  164. Velloso LA, Araújo EP, De Souza CT (2008) Diet-induced inflammation of the hypothalamus in obesity. Neuroimmunomodulation 15:189–193. doi:10.1159/000153423

    Article  CAS  PubMed  Google Scholar 

  165. Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F et al (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10(7):719–726. doi:10.1038/nm1058

    Article  CAS  PubMed  Google Scholar 

  166. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49(4):489–502. doi:10.1016/j.neuron.2006.01.022

    Article  CAS  PubMed  Google Scholar 

  167. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging. doi:10.1016/S0197-4580(00)00124-X

    PubMed Central  Google Scholar 

  168. Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ (2005) Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J Neuroinflammation 2:9. doi:10.1186/1742-2094-2-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Tarkowski E, Andreasen N, Tarkowski A, Blennow K (2003) Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74:1200–1205. doi:10.1136/jnnp.74.9.1200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB (2004) The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA: J Am Med Assoc 292(18):2237–2242. doi:10.1016/j.accreview.2004.12.135

    Article  CAS  Google Scholar 

  171. Krstic D, Knuesel I (2013) Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol 9:25–34. doi:10.1038/nrneurol.2012.236

    Article  CAS  PubMed  Google Scholar 

  172. Schwab C, Klegeris A, McGeer PL (2010) Inflammation in transgenic mouse models of neurodegenerative disorders. Biochim Biophys Acta 1802:889–902. doi:10.1016/j.bbadis.2009.10.013

    Article  CAS  PubMed  Google Scholar 

  173. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9(4):453–457. doi:10.1038/nm838

    Article  CAS  PubMed  Google Scholar 

  174. Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ (2005) Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specif- ically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice. J Neuroinflammation 2:23. doi:10.1186/1742-2094-2-23

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Hoozemans JJM, Rozemuller AJM, van Haastert ES, Eikelenboom P, van Gool WA (2011) Neuroinflammation in Alzheimer’s disease wanes with age. J Neuroinflammation 8:171. doi:10.1186/1742-2094-8-171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yaffe K, Weston AL, Blackwell T, Krueger KA (2009) The metabolic syndrome and development of cognitive impairment among older women. Arch Neurol 66(3):324–328. doi:10.1001/archneurol.2008.566

    Article  PubMed  PubMed Central  Google Scholar 

  177. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. doi:10.1016/S1474-4422(09)70062-6

    PubMed  Google Scholar 

  178. Hirsch EC, Vyas S, Hunot S (2012) Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord 18:S210–S212. doi:10.1016/S1353-8020(11)70065-7

    Article  PubMed  Google Scholar 

  179. Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol J-C, Lu L, Alvarez-Fischer D, Carrillo-de Sauvage MA et al (2011) Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci U S A 108(16):6632–6637. doi:10.1073/pnas.1017820108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ (2008) Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 29:1690–1701. doi:10.1016/j.neurobiolaging.2007.04.006

    Article  CAS  PubMed  Google Scholar 

  181. Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM, Hope AD, Pittman AM, Lashley T et al (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 127:420–430. doi:10.1093/brain/awh054

    Article  PubMed  Google Scholar 

  182. Waak J, Weber SS, Waldenmaier A, Görner K, Alunni-Fabbroni M, Schell H, Vogt-Weisenhorn D, Pham T-T et al (2009) Regulation of astrocyte inflammatory responses by the Parkinson’s disease-associated gene DJ-1. FASEB J: Off Publ Fed Am Soc Exp Biol 23:2478–2489. doi:10.1096/fj.08-125153

    Article  CAS  Google Scholar 

  183. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676):605–608. doi:10.1038/33416

    Article  CAS  PubMed  Google Scholar 

  184. Frank-Cannon TC, Tran T, Ruhn KA, Martinez TN, Hong J, Marvin M, Hartley M, Treviño I et al (2008) Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci 28:10825–10834. doi:10.1523/JNEUROSCI.3001-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Rodríguez-Navarro JA, Casarejos MJ, Menéndez J, Solano RM, Rodal I, Gómez A, Yébenes JGD, Mena MA (2007) Mortality, oxidative stress and tau accumulation during ageing in parkin null mice. J Neurochem 103:98–114. doi:10.1111/j.1471-4159.2007.04762.x

    PubMed  Google Scholar 

  186. Wang Q, Liu Y, Zhou J (2015) Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegeneration 4:19. doi:10.1186/s40035-015-0042-0

    Article  CAS  Google Scholar 

  187. Torrente D, Cabezas R, Avila MF, Garcia-Segura LM, Barreto GE, Guedes RC (2014) Cortical spreading depression in traumatic brain injuries: is there a role for astrocytes? Neurosci Lett 565:2–6. doi:10.1016/j.neulet.2013.12.058

    Article  CAS  PubMed  Google Scholar 

  188. J. Kriz (2013) Neuron-Glia Interaction in Neuroinflammation, 7, 75–89 doi:10.1007/978-1-4614-8313-7

  189. Verkhratsky A, Butt A (2013) Glial physiology and pathophysiology. Glial Physiol Pathophysiol. doi:10.1002/9781118402061

    Article  Google Scholar 

  190. Posada-Duque RA, Barreto GE, Cardona-Gomez GP (2014) Protection after stroke: cellular effectors of neurovascular unit integrity. Front Cell Neurosci 8:231. doi:10.3389/fncel.2014.00231

    Article  PubMed  PubMed Central  Google Scholar 

  191. Mucke L, Eddleston M (1993) Astrocytes in infectious and immune-mediated diseases of the central nervous system. FASEB J: Off Publ Fed Am Soc Exp Biol 7:1226–1232

    CAS  Google Scholar 

  192. Aschner M (1998) Immune and inflammatory responses in the CNS: modulation by astrocytes. Toxicol Lett 102–103:283–287. doi:10.1016/S0378-4274(98)00324-5

    Article  PubMed  Google Scholar 

  193. Kimelberg HK (2007) Supportive or information-processing functions of the mature protoplasmic astrocyte in the mammalian CNS? A critical appraisal. Neuron Glia Biol 3:181–189. doi:10.1017/S1740925X08000094

    Article  PubMed  PubMed Central  Google Scholar 

  194. Sonnewald U, Westergaard N, Schousboe A (1995) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Dev Neurosci 17(4):203–211

    Article  PubMed  Google Scholar 

  195. Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia. doi:10.1002/glia.20528

    PubMed  Google Scholar 

  196. Boyarsky G, Ransom B, Schlue WR, Davis MB, Boron WF (1993) Intracellular pH regulation in single cultured astrocytes from rat forebrain. Glia 8:241–248. doi:10.1002/glia.440080404

    Article  CAS  PubMed  Google Scholar 

  197. Westergaard N, Schousboe A, Sonnewald U, Petersen SB, Yu AC, Hertz L (1992) Regulatory role of astrocytes for neuronal biosynthesis and homeostasis of glutamate and GABA. Prog Brain Res 94:199–211

    Article  PubMed  Google Scholar 

  198. Owens T, Babcock AA, Millward JM, Toft-Hansen H (2005) Cytokine and chemokine inter-regulation in the inflamed or injured CNS. Brain Res Rev. doi:10.1016/j.brainresrev.2004.12.007

    PubMed  Google Scholar 

  199. Frontczak-Baniewicz M, Walski M (2006) Glial scar instability after brain injury. J Physiol Pharmacol 57:97–102

    PubMed  Google Scholar 

  200. Ransom B, Behar T, Nedergaard M (2003) New roles for astrocytes (stars at last). Trends Neurosci. doi:10.1016/j.tins.2003.08.006

    Google Scholar 

  201. Parpura V, Zorec R (2010) Gliotransmission: Exocytotic release from astrocytes. Brain Res Rev. doi:10.1016/j.brainresrev.2009.11.008

    Google Scholar 

  202. Anderson MF, Blomstrand F, Blomstrand C, Eriksson PS, Nilsson M (2003) Astrocytes and stroke: networking for survival? Neurochem Res 28:293–305. doi:10.1023/A:1022385402197

    Article  CAS  PubMed  Google Scholar 

  203. Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190. doi:10.1002/glia.1107

    Article  CAS  PubMed  Google Scholar 

  204. Araya R, Kudo M, Kawano M, Ishii K, Hashikawa T, Iwasato T, Itohara S, Terasaki T et al (2008) BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood-brain-barrier. Mol Cell Neurosci 38(3):417–430. doi:10.1016/j.mcn.2008.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR (2009) VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci U S A 106(6):1977–1982. doi:10.1073/pnas.0808698106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16(5):249–263. doi:10.1038/nrn3898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214. doi:10.1038/nrd1330

    Article  CAS  PubMed  Google Scholar 

  208. Clark RA, Valente AJ (2004) Nuclear factor kappa B activation by NADPH oxidases. Mech Ageing Dev 125:799–810. doi:10.1016/j.mad.2004.08.009

    Article  CAS  PubMed  Google Scholar 

  209. Freeman LR, Zhang L, Nair A, Dasuri K, Francis J, Fernandez-Kim SO, Bruce-Keller AJ, Keller JN (2013) Obesity increases cerebrocortical reactive oxygen species and impairs brainfunction. Free Radic Biol Med 56:226–233. doi:10.1016/j.freeradbiomed.2012.08.577

    Article  CAS  PubMed  Google Scholar 

  210. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN et al (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 114:1581–1589. doi:10.1111/j.1471-4159.2010.06865.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol. doi:10.1016/j.it.2007.01.005

    PubMed  Google Scholar 

  212. Herx LM, Yong VW (2001) Interleukin-1 beta is required for the early evolution of reactive astrogliosis following CNS lesion. J Neuropathol Exp Neurol 60:961–971

    Article  CAS  PubMed  Google Scholar 

  213. Herx LM, Rivest S, Yong VW (2000) Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol (Baltimore, MD: 1950) 165:2232–2239. doi:10.4049/jimmunol.165.4.2232

    Article  CAS  Google Scholar 

  214. Mason JL, Suzuki K, Chaplin DD, Matsushima GK (2001) Interleukin-1beta promotes repair of the CNS. J Neurosci 21:7046–7052

    CAS  PubMed  Google Scholar 

  215. Penkowa M, Moos T, Carrasco J, Hadberg H, Molinero A, Bluethmann H, Hidalgo J (1999) Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice. Glia 25:343–357. doi:10.1002/(SICI)1098-1136(19990215)25:4<343::AID-GLIA4>3.0.CO;2-V

    Article  CAS  PubMed  Google Scholar 

  216. Swartz KR, Liu F, Sewell D, Schochet T, Campbell I, Sandor M, Fabry Z (2001) Interleukin-6 promotes post-traumatic healing in the central nervous system. Brain Res 896:86–95. doi:10.1016/S0006-8993(01)02013-3

    Article  CAS  PubMed  Google Scholar 

  217. Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW (2004) Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem. doi:10.1111/j.1471-4159.2004.02420.x

    PubMed  Google Scholar 

  218. Bsibsi M, Persoon-Deen C, Verwer RWH, Meeuwsen S, Ravid R, Van Noort JM (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53:688–695. doi:10.1002/glia.20328

    Article  PubMed  Google Scholar 

  219. Tran PB, Miller RJ (2003) Chemokine receptors: signposts to brain development and disease. Nat Rev Neurosci 4:444–455

    Article  CAS  PubMed  Google Scholar 

  220. Ambrosini E, Aloisi F (2004) Chemokines and glial cells: a complex network in the central nervous system. Neurochem Res. doi:10.1023/B:NERE.0000021246.96864.89

    PubMed  Google Scholar 

  221. Babcock AA, Kuziel WA, Rivest S, Owens T (2003) Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 23:7922–7930

    CAS  PubMed  Google Scholar 

  222. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924. doi:10.1038/nn1715

    Article  CAS  PubMed  Google Scholar 

  223. Gimenez MA, Sim J, Archambault AS, Klein RS, Russell JH (2006) A tumor necrosis factor receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. Am J Pathol 168:1200–1209. doi:10.2353/ajpath.2006.050332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Han HS, Suk K (2005) The function and integrity of the neurovascular unit rests upon the integration of the vascular and inflammatory cell systems. Curr Neurovasc Res. doi:10.2174/156720205774962647

    PubMed  Google Scholar 

  225. Koehler RC, Gebremedhin D, Harder DR (2006) Role of astrocytes in cerebrovascular regulation. J Appl Physiol (Bethesda, MD: 1985) 100:307–317. doi:10.1152/japplphysiol.00938.2005

    Article  CAS  Google Scholar 

  226. Prat A, Biernacki K, Wosik K, Antel JP (2001) Glial cell influence on the human blood-brain barrier. Glia 36:145–155. doi:10.1002/glia.1104

    Article  CAS  PubMed  Google Scholar 

  227. Van Kralingen C, Kho DT, Costa J, Angel CE, Graham ES (2013) Exposure to inflammatory cytokines IL-1β and TNFα induces compromise and death of astrocytes; implications for chronic neuroinflammation. PLoS One 8:e0084269. doi:10.1371/journal.pone.0084269

    Article  CAS  Google Scholar 

  228. Journiac N, Jolly S, Jarvis C, Gautheron V, Rogard M, Trembleau A, Blondeau J-P, Mariani J et al (2009) The nuclear receptor ROR(alpha) exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes. Proc Natl Acad Sci U S A 106:21365–21370. doi:10.1073/pnas.0911782106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Le Dréau G, Kular L, Nicot AB, Calmel C, Melik-Parsadaniantz S, Kitabgi P, Laurent M, Martinerie C (2010) NOV/CCN3 upregulates CCL2 and CXCL1 expression in astrocytes through β1 and β5 integrins. Glia 58:1510–1521. doi:10.1002/glia.21025

    PubMed  Google Scholar 

  230. Medeiros R, LaFerla FM (2013) Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol. doi:10.1016/j.expneurol.2012.10.007

    PubMed  Google Scholar 

  231. Kim KC, Hyun Joo S, Shin CY (2011) CPEB1 modulates lipopolysaccharide-mediated iNOS induction in rat primary astrocytes. Biochem Biophys Res Commun 409:687–692. doi:10.1016/j.bbrc.2011.05.065

    Article  CAS  PubMed  Google Scholar 

  232. Koyama Y, Mizobata T, Yamamoto N, Hashimoto H, Matsuda T, Baba A (1999) Endothelins stimulate expression of cyclooxygenase 2 in rat cultured astrocytes. J Neurochem 73:1004–1011. doi:10.1046/j.1471-4159.1999.0731004.x

    Article  CAS  PubMed  Google Scholar 

  233. Echeverria V, Clerman A, Dore S (2005) Stimulation of PGE receptors EP2 and EP4 protects cultured neurons against oxidative stress and cell death following beta-amyloid exposure. Eur J Neurosci 22(9):2199–2206. doi:10.1111/j.1460-9568.2005.04427.x

    Article  PubMed  Google Scholar 

  234. Luheshi NM, Rothwell NJ, Brough D (2009) Dual functionality of interleukin-1 family cytokines: implications for anti-interleukin-1 therapy. Br J Pharmacol 157:1318–1329. doi:10.1111/j.1476-5381.2009.00331.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Rothhammer V, Quintana FJ (2015) Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol. doi:10.1007/s00281-015-0515-3

    Google Scholar 

  236. Gadani SP, Cronk J (2013) Interleukin-4: a cytokine to remember. J Immunol 189:4213–4219. doi:10.4049/jimmunol.1202246.Interleukin-4

    Article  CAS  Google Scholar 

  237. Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183(6):2627–2634. doi:10.1084/jem.183.6.2627

    Article  CAS  PubMed  Google Scholar 

  238. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765. doi:10.1146/annurev.immunol.19.1.683

    Article  CAS  PubMed  Google Scholar 

  239. de Waal Malefyt R, Figdor CG, Huijbens R, Mohan-Peterson S, Bennett B, Culpepper J, Dang W, Zurawski G et al (1993) Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J Immunol (Baltimore, MD: 1950) 151(11):6370–6381

    Google Scholar 

  240. Wynn TA (2003) IL-13 effector functions. Annu Rev Immunol 21:425–456. doi:10.1146/annurev.immunol.21.120601.141142

    Article  CAS  PubMed  Google Scholar 

  241. Jensen CJ, Massie A, De Keyser J (2013) Immune players in the CNS: the astrocyte. J NeuroImmune Pharmacol 8:824–839. doi:10.1007/s11481-013-9480-6

    Article  PubMed  Google Scholar 

  242. Gorina R, Font-Nieves M, Márquez-Kisinousky L, Santalucia T, Planas AM (2010) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–255. doi:10.1002/glia.21094

    Article  Google Scholar 

  243. Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75(2):163–189. doi:10.1189/jlb.0603252

    Article  CAS  PubMed  Google Scholar 

  244. Pfeffer K (2003) Biological functions of tumor necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev 14:185–191. doi:10.1016/S1359-6101(03)00022-4

    Article  CAS  PubMed  Google Scholar 

  245. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14(6):681–687. doi:10.1038/nm1781

    CAS  PubMed  PubMed Central  Google Scholar 

  246. McKimmie CS, Graham GJ (2010) Astrocytes modulate the chemokine network in a pathogen-specific manner. Biochem Biophys Res Commun 394:1006–1011. doi:10.1016/j.bbrc.2010.03.111

    Article  CAS  PubMed  Google Scholar 

  247. Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K et al (2006) TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia 53:248–256. doi:10.1002/glia.20278

    Article  PubMed  Google Scholar 

  248. Calderon TM, Eugenin EA, Lopez L, Kumar SS, Hesselgesser J, Raine CS, Berman JW (2006) A role for CXCL12 (SDF-1alpha) in the pathogenesis of multiple sclerosis: regulation of CXCL12 expression in astrocytes by soluble myelin basic protein. J Neuroimmunol 177:27–39. doi:10.1016/j.jneuroim.2006.05.003

    Article  CAS  PubMed  Google Scholar 

  249. Tohyama M, Sayama K, Komatsuzawa H, Hanakawa Y, Shirakata Y, Dai X, Yang L, Tokumaru S et al (2007) CXCL16 is a novel mediator of the innate immunity of epidermal keratinocytes. Int Immunol 19:1095–1102. doi:10.1093/intimm/dxm083

    Article  CAS  PubMed  Google Scholar 

  250. Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Nuerol 1:232–241. doi:10.1016/S1474-4422(02)00102-3

    Article  CAS  Google Scholar 

  251. Meda L (2001) Glial activation in Alzheimer’s disease: the role of AÎ2 and its associated proteins. Neurobiol Aging 22(6):885–893. doi:10.1016/S0197-4580(01)00307-4

    Article  CAS  PubMed  Google Scholar 

  252. DeWitt DA, Perry G, Cohen M, Doller C, Silver J (1998) Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exp Neurol 149(2):329–340. doi:10.1006/exnr.1997.6738

    Article  CAS  PubMed  Google Scholar 

  253. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25(5):663–674. doi:10.1016/j.neurobiolaging.2004.01.007

    Article  CAS  PubMed  Google Scholar 

  254. Bamberger ME, Landreth GE (2001) Microglial interaction with B-amyloid: implications for the pathogenesis of Alzheimer’s disease. Microsc Res Tech 70:59–70. doi:10.1002/jemt.1121

    Article  Google Scholar 

  255. Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang H-Y (2003) Astrocytes accumulate a beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971(2):197–209. doi:10.1016/S0006-8993(03)02361-8

    Article  CAS  PubMed  Google Scholar 

  256. Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58(7):831–838. doi:10.1002/glia.20967

    PubMed  Google Scholar 

  257. Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, Savva G, Brayne C et al (2010) Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging 31(4):578–590. doi:10.1016/j.neurobiolaging.2008.05.015

    Article  CAS  PubMed  Google Scholar 

  258. Pihlaja R, Koistinaho J, Malm T, Sikkila H, Vainio S, Koistinaho M (2008) Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer’s disease. Glia 56(2):154–163. doi:10.1002/glia.20599

    Article  PubMed  Google Scholar 

  259. Pihlaja R, Koistinaho J, Kauppinen R, Sandholm J, Tanila H, Koistinaho M (2011) Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes. Glia 59(11):1643–1657. doi:10.1002/glia.21212

    Article  PubMed  Google Scholar 

  260. Haughey, Mattson (2003) Alzheimer’s amyloid β-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neruomol Med 3:173–180. doi:10.1385/NMM:3:3:173

    Article  Google Scholar 

  261. Johnston JM, Burnett P, Thomas AP, Tezapsidis N (2006) Calcium oscillations in type-1 astrocytes, the effect of a presenilin 1 (PS1) mutation. Neurosci Lett 395(2):159–164. doi:10.1016/j.neulet.2005.10.088

    Article  CAS  PubMed  Google Scholar 

  262. McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Discord. doi:10.1002/mds.21751

    Google Scholar 

  263. Mena MA, García de Yébenes J (2008) Glial cells as players in parkinsonism: the “good,” the “bad,” and the “mysterious” glia. Neuroscientist: Rev J Bringing Neurobiol, Neurol Psychiatry 14(6):544–560. doi:10.1177/1073858408322839

    Article  CAS  Google Scholar 

  264. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 26(1):6–17. doi:10.1002/mds.23455

    Article  PubMed  Google Scholar 

  265. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7(4):399–412. doi:10.1016/j.nurt.2010.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Barreto GE, Iarkov A, Moran VE (2014) Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease. Front Aging Neurosci 6:340. doi:10.3389/fnagi.2014.00340

    PubMed  Google Scholar 

  267. Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52(1):1–6. doi:10.1016/0306-4522(93)90175-F

    Article  CAS  PubMed  Google Scholar 

  268. Song YJC, Halliday GM, Holton JL, Sullivan SO, McCann H, Path B, Lashley T, Lees AJ et al (2009) Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 68(10):1073–1083. doi:10.1097/NEN.0b013e3181b66f1b

    Article  CAS  PubMed  Google Scholar 

  269. Braak H, Sastre M, Del Tredici K (2007) Development of α-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 114(3):231–241. doi:10.1007/s00401-007-0244-3

    Article  CAS  PubMed  Google Scholar 

  270. Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E et al (2010) Direct transfer of α-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285(12):9262–9272. doi:10.1074/jbc.M109.081125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Desplats P, Lee H-J, Bae E-J, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E et al (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 106:13010–13015. doi:10.1073/pnas.0903691106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Bartels AL, Willemsen ATM, Doorduin J, de Vries EFJ, Dierckx RA, Leenders KL (2010) [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord 16(1):57–59. doi:10.1016/j.parkreldis.2009.05.005

    Article  CAS  PubMed  Google Scholar 

  273. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, Oertel W et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21(2):404–412. doi:10.1016/j.nbd.2005.08.002

    Article  CAS  PubMed  Google Scholar 

  274. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20. doi:10.1007/PL00007400

    Article  CAS  PubMed  Google Scholar 

  275. Colangelo AM, Alberghina L, Papa M (2014) Astrogliosis as a therapeutic target for neurodegenerative diseases. Neurosci Lett. doi:10.1016/j.neulet.2014.01.014

    PubMed  Google Scholar 

  276. Chen Y, Vartiainen NE, Ying W, Chan PH, Koistinaho J, Swanson RA (2001) Astrocytes protect neurons from nitric oxide toxicity by a glutathione-dependent mechanism. J Neurochem 77:1601–1610. doi:10.1046/j.1471-4159.2001.00374.x

    Article  CAS  PubMed  Google Scholar 

  277. Sarafian TA, Montes C, Imura T, Qi J, Coppola G, Geschwind DH, Sofroniew MV (2010) Disruption of astrocyte STAT3 signaling decreases mitochondrial function and increases oxidative stress in vitro. PLoS ONE 5:e9532. doi:10.1371/journal.pone.0009532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  278. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406

    CAS  PubMed  Google Scholar 

  279. Swanson RA, Ying W, Kauppinen TM (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4:193–205. doi:10.2174/1566524043479185

    Article  CAS  PubMed  Google Scholar 

  280. Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci: Off J Soc Neurosci 28:13574–13581. doi:10.1523/JNEUROSCI.4099-08.2008

    Article  CAS  Google Scholar 

  281. Avila Rodriguez M, Garcia-Segura LM, Cabezas R, Torrente D, Capani F, Gonzalez J, Barreto GE (2014) Tibolone protects T98G cells from glucose deprivation. J Steroid Biochem Mol Biol 144 Pt B:294–303. doi:10.1016/j.jsbmb.2014.07.009

    Article  PubMed  CAS  Google Scholar 

  282. Cabezas R, Avila MF, Gonzalez J, El-Bacha RS, Barreto GE (2015) PDGF-BB protects mitochondria from rotenone in T98G cells. Neurotox Res 27(4):355–367. doi:10.1007/s12640-014-9509-5

    Article  CAS  PubMed  Google Scholar 

  283. Lin JH-C, Lou N, Kang N, Takano T, Hu F, Han X, Xu Q, Lovatt D et al (2008) A central role of connexin 43 in hypoxic preconditioning. J Neurosci Off J Soc Neurosci 28:681–695. doi:10.1523/JNEUROSCI.3827-07.2008

    Article  CAS  Google Scholar 

  284. Avila-Rodriguez M, Garcia-Segura LM, Hidalgo-Lanussa O, Baez E, Gonzalez J, Barreto GE (2016) Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression. Mol Cell Endocrinol 433:35–46. doi:10.1016/j.mce.2016.05.024

    Article  CAS  PubMed  Google Scholar 

  285. Toro-Urrego N, Garcia-Segura LM, Echeverria V, Barreto GE (2016) Testosterone protects mitochondrial function and regulates neuroglobin expression in astrocytic cells exposed to glucose deprivation. Front Aging Neurosci 8:152. doi:10.3389/fnagi.2016.00152

    Article  PubMed  PubMed Central  Google Scholar 

  286. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH et al (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308. doi:10.1016/S0896-6273(00)80781-3

    Article  CAS  PubMed  Google Scholar 

  287. Chen Y, Swanson RA (2003) Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149. doi:10.1097/01.WCB.0000044631.80210.3C

    Article  PubMed  Google Scholar 

  288. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. doi:10.1007/s00401-009-0619-8

    Article  PubMed  Google Scholar 

  289. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. doi:10.1016/j.tins.2009.08.002

    PubMed  PubMed Central  Google Scholar 

  290. Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist: Rev J Bringing Neurobiol, Neurol Psychiatry 11:400–407. doi:10.1177/1073858405278321

    Article  CAS  Google Scholar 

  291. Cheng S, Hou J, Zhang C, Xu C, Wang L, Zou X, Yu H, Shi Y et al (2015) Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. Sci Rep 5:10535. doi:10.1038/srep10535

    Article  PubMed  PubMed Central  Google Scholar 

  292. Noble W, Garwood CJ, Hanger DP (2009) Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding. Prion 3:78–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Castaño A, Herrera AJ, Cano J, Machado A (2002) The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-alpha IL-1beta IFN-gamma. J Neurochem 81:150–157. doi:10.1046/j.1471-4159.2002.00799.x

    Article  PubMed  Google Scholar 

  294. Di Matteo V, Pierucci M, Di Giovanni G, Di Santo A, Poggi A, Benigno A, Esposito E (2006) Aspirin protects striatal dopaminergic neurons from neurotoxin-induced degeneration: an in vivo microdialysis study. Brain Res 1095:167–177. doi:10.1016/j.brainres.2006.04.013

    Article  CAS  PubMed  Google Scholar 

  295. Mohanakumar KP, Muralikrishnan D, Thomas B (2000) Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced neurotoxicity. Brain Res 864:281–290

    Article  CAS  PubMed  Google Scholar 

  296. Starke RM, Chalouhi N, Ding D, Hasan DM (2015) Potential role of aspirin in the prevention of aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis 39:332–342. doi:10.1159/000381137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Clària J, Serhan CN (1995) Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci U S A 92:9475–9479. doi:10.1073/pnas.92.21.9475

    Article  PubMed  PubMed Central  Google Scholar 

  298. Echeverria V, Yarkov A, Aliev G (2016) Positive modulators of the alpha7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer’s disease. Prog Neurobiol. doi:10.1016/j.pneurobio.2016.01.002

    PubMed  Google Scholar 

  299. Barreto GE, Santos-Galindo M, Garcia-Segura LM (2014) Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury. Front Aging Neurosci 6:132. doi:10.3389/fnagi.2014.00132

    PubMed  PubMed Central  Google Scholar 

  300. Barreto G, Santos-Galindo M, Diz-Chaves Y, Pernia O, Carrero P, Azcoitia I, Garcia-Segura LM (2009) Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormones. Endocrinology 150(11):5010–5015. doi:10.1210/en.2009-0352

    Article  CAS  PubMed  Google Scholar 

  301. Barreto G, Veiga S, Azcoitia I, Garcia-Segura LM, Garcia-Ovejero D (2007) Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone. Eur J Neurosci 25(10):3039–3046. doi:10.1111/j.1460-9568.2007.05563.x

    Article  PubMed  Google Scholar 

  302. Lanussa OH, Avila-Rodriguez M, Garcia-Segura LM, Gonzalez J, Echeverria V, Aliev G, Barreto GE (2016) Microglial dependent protective effects of neuroactive steroids. CNS Neurol Disord Drug Targets 15(2):242–249

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia

    Cynthia Alexandra Martin-Jiménez, Diana Milena Gaitán-Vaca, Janneth González & George E. Barreto

  2. Facultad de Ciencias de la Salud, Universidad San Sebastián, General Cruz, 1577, Concepción, Chile

    Valentina Echeverria

  3. Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile

    George E. Barreto

Authors
  1. Cynthia Alexandra Martin-Jiménez
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  2. Diana Milena Gaitán-Vaca
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  3. Valentina Echeverria
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  4. Janneth González
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  5. George E. Barreto
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Correspondence to Janneth González or George E. Barreto.

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Martin-Jiménez, C.A., Gaitán-Vaca, D.M., Echeverria, V. et al. Relationship Between Obesity, Alzheimer’s Disease, and Parkinson’s Disease: an Astrocentric View. Mol Neurobiol 54, 7096–7115 (2017). https://doi.org/10.1007/s12035-016-0193-8

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  • DOI: https://doi.org/10.1007/s12035-016-0193-8

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