[Frontiers in Bioscience, Scholar, 7, 189-204, June 1, 2015]

Ageing, neuroinflammation and neurodegeneration

Roberta J Ward 1, 2 , David T. Dexter 1 , Robert R. Crichton 2

1Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Imperial College, London UK. 2Universite catholique de Louvain, Belgium


1. Abstract
2. Introduction
3. Role of iron in the brain
4. Role of microglia in the brain
5. Effect of Ageing on brain iron content and neuroinflammation
    5.1. Ageing and iron accumulation
    5.2. Ageing and inflammation
6. Neurodegeneration and iron accumulation
    6.1. Iron accumulation in Parkinson’s disease
    6.2. Iron accumulation in Alzheimer’s disease
    6.3. Iron accumulation in Multiple sclerosis
    6.4. Iron accumulation in Friedreich’s ataxia
7. Neuroinflammation in neurodegenerative diseases
    7.1. Neuroinflammation in Parkinson’s disease
    7.2. Neuroinflammation in Alzheimer’s disease
    7.3. Neuroinflammation in Multiple sclerosis
8. Therapeutic strategies to reduce iron content and neuroinflammation in neurodegenerative diseases
    8.1. Chelation of excess iron in Parkinson’s disease
    8.2. Chelation of excess iron Alzheimer’s disease
    8.3. The use of anti-inflammatory drugs in neurodegenerative diseases
9. Conclusion
10. References


During ageing, different iron complexes accumulate in specific brain regions which are associated with motor and cognitive dysfunction. In neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, changes in local iron homoeostasis result in altered cellular iron distribution and accumulation, ultimately inducing neurotoxicity. The use of iron chelators which are able to penetrate the blood brain barrier and reduce excessive iron accumulation in specific brain regions have been shown to reduce disease progression in both Parkinson’s disease and Friedreich’s Ataxia. Neuroinflammation often occurs in neurodegenerative diseases, which is mainly sustained by activated microglia exhibiting the M1 phenotype. Such inflammation contributes to the disease progression. Therapeutic agents which reduce such inflammation, e.g. taurine compounds, may ameliorate the inflammatory process by switching the microglia from a M1 to a M2 phenotype.


1. R.R.Crichton, and R.J.Ward: Metal based neurodegeneration. From molecular mechanisms to therapeutic strategies. Publ. JWiley & Son pp1-423. (2014)

2. Ward, R.J., F.A. Zucca, J.H. Duyn, R.R. Crichton, & L. Zecca : The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13, 1045-60 (2014)
DOI: 10.1016/S1474-4422(14)70117-6

3. Mittelbronn, M., K. Dietz, H.J. Schluesener, & R. Meyermann : Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol. 101, 249-55 (2001)

4. London, A., M. Cohen, & M. Schwartz : Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci. 7, 34 (2013)
DOI: 10.3389/fncel.2013.00034

5. Kettenmann, H., F. Kirchhoff , & A. Verkhratsky : Microglia: new roles for the synaptic stripper. Neuron. 77, 10-8 (2013).
DOI: 10.1016/j.neuron.2012.12.023

6. Wake, H., A.J. Moorhouse , S. Jinno, S. Kohsaka, & J. Nabekura : Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 29, 3974-80 (2009)
DOI: 10.1523/JNEUROSCI.4363-08.2009

7. Ohsawa, K., Y. Irino, Y. Nakamura, C. Akazawa, K. Inoue, & S. Kohsaka: Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. See comment in PubMed Commons belowGlia. 55, 604-16 (2007).
DOI: 10.1002/glia.20489

8. Olsen, J.K., & S.D. Miller: Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunology 173, 3916-3924 (2004).

9. Kettenmann, H., U.K. Hanisch, M. Noda, & A. Verkhratsky: Physiology of microglia. Physiol Rev. 91, 461-553 (2011)
DOI: 10.1152/physrev.00011.2010

10. Pocock, J.M., & H. Kettenmann: Neurotransmitter receptors on microglia. Trends in Neurosci 30, 527-535 (2007).
DOI: 10.1016/j.tins.2007.07.007

11. Fumagalli, M., D. Lecca, & M.P. Abbracchio: (2011) Role of purinergic signalling in neuro-immune cells and adult neural progenitors. Frontiers in Biosci 16, 2326-2341 (2011)

12. Brody, H: The aging brain Acta Neurol Scand Suppl. 137, 40-4 (1992)

13. Coleman, P. D. & D.G. Flood: Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol Aging 8, 521–45 (1987)
DOI: 10.1016/0197-4580(87)90127-8

14. Ball, M.J: Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A quantitative study. Acta Neuropathol. (Berl.) 37, 111–18 (1977)
DOI: 10.1007/BF00692056

15. Pakkenberg, B., & H.J. Gundersen: Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384, 312–20 (1997)
DOI: 10.1002/(SICI)1096-9861(19970728)38 4:2<312::AID-CNE10>3.0.CO;2-K

16. West, M.J., P.D. Coleman, D.G. Flood, & J.C. Troncoso: Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344, 769–72 (1994)

17. Burke, S.N. & C.A. Barnes: Neural plasticity in the ageing brain. Nature Reviews Neurosci 7, 30-40 (2006)
DOI: 10.1038/nrn1809

18. Connor, J.R., & S.L. Menzies: Relationship of iron to oligodentrocytes and myelination. Glia 17, 83-3 (1996)
DOI:10.1002/(SICI)1098-1136(199606)17:2< 83::AID-GLIA1>3.0.CO;2-7

19. Godbout, J.P., J. Chen, J. Abraham, A.F. Richwine, B.M. Berg, K.W. Kelley, & R.W. Johnson: Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19, 1329–31 (2005)

20. Sparkman, N.L., & R.W. Johnson: Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress Neuroimmunomodulation 15, 323-30 (2008)

21. Lee C.K., R.G. Klopp, R. Weindruch, & T.A. Prolla: Gene expression profile of aging and its retardation by caloric restriction. Science 285, 1390–93 (1999)

22. Sama, D.M., & C.M. Norris: Calcium dysregulation and neuroinflammation: Discrete and integrated mechanisms for age-related synaptic dysfunction. Ageing Res Rev 12, 982-95 (2013)

23. Singhal, G., E.J. Jaehne, F. Corrigan, C. Toben, & B.T. Baune: Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci. 8, 315 (2014)
DOI: 10.3389/fnins.2014.00315

24. Norden, DM., & J.P. Godbout: Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation. Neuropathol Appl Neurobiol. 39, 19–34 (2013)

25. VanGuilder, HD., G.V. Bixler, R.M. Brucklacher, J.A. Farley, H. Yan, J.P. Warrington, W.E. Sonntag & W.M. Freeman: Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation. 8, 138 (2011)
DOI: 10.1186/1742-2094-8-138

26. Crichton, R.R. & R.J. Ward: Metal based neurodegeneration. From molecular mechanisms to therapeutic strategies. J Wiley and Son pp. 1-227, Chichester, UK. (2006)

27. Kwok, J.B: Role of epigenetics in Alzheimer’s and Parkinson’s disease. Epigenomics 2, 671-82 (2010)
DOI: 10.2217/epi.10.43

28. Catalá, A. Lipid peroxidation of membrane phospholipids generates hydroxyl-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids 157, 1-11 (2009)
DOI: 10.1016/j.chemphyslip.2008.09.004

29. Horowitz, M.P. & J.T. Greenamyre: Mitochondrial iron metabolism and its role in neurodegeneration. J Alzheimers Dis 20, S551-568 (2010)

30. Li, W.J., H. Jiang., N. Song, & J.X. Xie: Dose- and time-dependent alpha-synuclein aggregation induced by ferric iron in SK-N-SH cells. Neurosci Bull 26, 205–210 (2010).
DOI: 10.1007/s12264-010-1117-7

31. Yamamoto, A., R.W. Shin, K. Hasegawa, H. Naiki, H. Sato, F. Yoshimasu, & T. Kitamoto: Iron (III) induces aggregation of hyperphosphorylated tau & its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem. 82, 1137-47 (2002)
DOI: 10.1046/j.1471-4159.2002.t01-1-01061.x

32. Liu, Y., & J.R. Connor: Iron and ER stress in neurodegenerative disease. Biometals. 25, 837-45 (2012)

33. Dexter, D.T., F.R.Wells, F. Agid, Y. Agid, A.J. Lees, P. Jenner & C.D.Marsden: Increased nigral iron content in postmortem parkinsonian brain. Lancet. 2(8569), 1219-20, (1987)
DOI: 10.1016/S0140-6736(87)91361-4

34. Dexter, D.T., A. Carayon, F. Javoy-Agid, Y. Agid, F.R. Wells, S.E. Daniel, A.J. Lees, P. Jenner, & C.D. Marsden: Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114, 1953-75 (1991)
DOI: 10.1093/brain/114.4.1953

35. Griffiths, P.D., B.R. Dobson, G.R. Jones, & D.T. Clarke: Iron in the basal ganglia in Parkinson’s disease. An in vitro study using extended X-ray absorption fine structure and cryo-electron microscopy. Brain 122, 667-73 (1999)
DOI: 10.1093/brain/122.4.667

36.Jellinger, K., W. Paulus, I. Grundke-Iqbal, P. Riederer, & M.B. Youdim: Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases. J Neural Transm Park Dis Dement Sect.2, 327-40 (1999)
DOI: 10.1007/BF02252926

37. Castellani, RJ., S.L. Siedlak, G. Perry, & M.A. Smith: Sequestration of iron by Lewy bodies in Parkinson’s disease. Acta Neuropathol. 100, 111-4 (2000)
DOI: 10.1007/s004010050001

38. El-Agnaf, OM., & G.B. Irvine: Aggregation and neurotoxicity of alpha-synuclein and related peptides. Biochem Soc Trans. 30, 559-65 (2002)
DOI: 10.1042/BST0300559

39. Roberts, BR., T.M. Ryan, A.L. Bush, C.L. Masters, & J.A. Duce: The role of metallobiology and amyloid-β peptides in Alzheimer’s disease. J Neurochem. 120 Suppl 1, 149-66 (2012)
DOI: 10.1111/j.1471-4159.2011.07500.x

40. Sayre, LM., G. Perry, P.L. Harris, Y. Liu, K.A. Schubert, & M.A. Smith: In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem 74, 270-9 (2000)
DOI: 10.1046/j.1471-4159.2000.0740270.x

41. Perry, G., A. Nunomura, K. Hirai, X. Zhu, M. Pérez, J. Avila, R.J. Castellani, C.S. Atwood, G. Aliev, L.M. Sayre, A. Takeda, & M.A. Smith: Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases? Free Radic Biol Med 33, 1475-9 (2002)
DOI: 10.1016/S0891-5849(02)01113-9

42. Guillemot, J., M. Canuel, R. Essalmani, A. Prat, & N.G. Seidah: Implication of the proprotein convertases in iron homeostasis: PC7 sheds human transferrin receptor 1 and furin activates hepcidin. Hepatology 57, 2514-24 (2013)
DOI: 10.1002/hep.26297

43. Silvestri, L., & C. Camaschella: A potential pathogenetic role of iron in Alzheimer’s disease. J Cell Mol Med 12(5A), 1548-50 (2008)
DOI: 10.1111/j.1582-4934.2008.00356.x

44. Altamura, S., & M.U.Muckenthaler: Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis 16, 879-95 (2009)

45. Rogers, JT., J.D. Randall, C.M. Cahill, P.S. Eder, X. Huang, H. Gunshin, L. Leiter, J. McPhee, S.S. Sarang, T. Utsuki N.H. Greig, D.K. Lahiri, R.E. Tanzi, A.L. Bush, T. Giordano, & S.R. Gullans: An iron-responsive element type II in the 5’-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 277, 45518-28 (2002)
DOI: 10.1074/jbc.M207435200

46. Lassmann, H., J. van Horssen, & D. Mahad: Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 8, 647-56 (2012)
DOI: 10.1038/nrneurol.2012.168

47. Neema, M., A. Arora, B.C. Healy, Z.D. Guss, S.D. Brass, Y. Duan, G.J. Buckle, B.I. Glanz, L. Stazzone, S.J. Khoury, H.L. Weiner, C.R. Guttmann, & R. Bakshi: Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis. J Neuroimaging 19, 3-8 (2009)
DOI: 10.1111/j.1552-6569.2008.00296.x

48. Ropele, S., W. de Graaf, M. Khalil, M.P. Wattjes, C. Langkammer, M.A. Rocca, A. Rovira, J. Palace, F. Barkhof, M. Filippi, & F. Fazekas: MRI assessment of iron deposition in multiple sclerosis. J Magn Reson Imaging 34, 13-21 (2011)
DOI: 10.1002/jmri.22590

49. Williams, R., C.L. Buchheit, N.E. Berman, & S.M. LeVine: Pathogenic implications of iron accumulation in multiple sclerosis. J Neurochem 120, 7-25 (2012)
DOI: 10.1111/j.1471-4159.2011.07536.x

50. Campuzano, V., L. Montermini, M.D. Moltò, L. Pianese, M. Cossée, F. Cavalcanti, E. Monros, F. Rodius, F. Duclos, A. Monticelli, F. Zara, J. Ca-izares,, H. Koutnikova, S.I. Bidichandani, C. Gellera, A. Brice, P. Trouillas, G. De Michele, A. Filla, R. De Frutos, F. Palau, P.I. Patel, S. Di Donato, J.L. Mandel, S. Cocozza, M. Koenig, & M. Pandolfo: Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 271, 1423-7 (1996)
DOI: 10.1126/science.271.5254.1423

51. Pandolfo, M: Friedreich ataxia: new pathways. J Child Neurol 27, 1204-11 (2012)
DOI: 10.1177/0883073812448534

52. Henka, M.T., P. Markus, & E. Latz: Innate immune activation in neurodegenerative disease. Nat Review Immunol 14, 463-477 (2014)
DOI: 10.1038/nri3705

53. Sastre, M., L. Katsouri, A. Birch, A. Renziehausen, D.T. Dexter, R.R. Crichton & R.J. Ward: Neuroinflammation in Alzheimer’s, Parkinson’s and Huntington Diseases in Neuroimmunology, Ed Amor S. & Woodroofe N. Publ. Wiley and Son, Chichester, UK. in press 2014

54. Pisanu, A., D. Lecca, G. Mulas, J. Wardas, G. Simbula, S. Spiga, & A.R. Carta: Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis. 71, 280-91 (2014)
DOI: 10.1016/j.nbd.2014.08.011

55. McGeer, E.G., & P.L.McGeer: Neuroinflammation in Alzheimer’s disease and mild cognitive impairment: a field in its infancy. J Alzheimers Dis 19, 355-61 (2010)

56. Varnum, M.M., & T. Ikezu: The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz).60, 251-66 (2012)
DOI: 10.1007/s00005-012-0181-2

57. Wilcock, D.M.: A changing perspective on the role of neuroinflammation in Alzheimer’s disease Int J Alzheimers Dis 495243, (2012)

58. Compston, A., & A. Coles: Multiple sclerosis. Lancet. 372, 1502-17 (2008)

59. Dexter, D.T., R.J. Ward, A. Florence, P. Jenner, R.R. Crichton: Effects of desferrithiocin and its derivatives on peripheral iron and striatal dopamine and 5-hydroxytryptamine metabolism in the ferrocene-loaded rat. Biochem Pharmacol. 58, 151-5 (1999)
doi: 10.1016/S0006-2952(99)00079-9

60. Crichton, RR., & R.J. Ward: An overview of iron metabolism: molecular and cellular criteria for the selection of iron chelators. Curr Med Chem.10, 997-1004 (2003)

61. Dexter, D.T., S.A. Statton, C., Whitmore, W. Freinbichler, P. Weinberger, K.F. Tipton, L. Della Corte, R.J. Ward, & R.R. Crichton: Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson’s disease after peripheral administration J Neural Transm 118, 223-31 (2011)

DOI: 10.1007/s00702-010-0531-3

62. Boddaert, N, K.H. Le Quan Sang, A. Rötig, A. Leroy-Willig, S. Gallet, F. Brunelle, D. Sidi, J.C. Thalabard, A. Munnich, & Z.I. Cabantchik: Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 110, 401-8 (2007)
DOI: 10.1182/blood-2006-12-065433

63. Kwiatkowski, A., G. Ryckewaert, P. Jissendi Tchofo, C. Moreau, I. Vuillauma, P.F. Chinnery, A. Destee, L. Defebvre, & D. Devos: Long term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation. Parkinsonism and Related Disorders 18, 110-12 (2010)

64. Devos, D., C. Moreau, J.C. Devedjian, J. Kluza, C. Laloux, A. Jonneaux, M. Petrault, G. Ryckewaert, G. Garçon, N. Rouaix, A. Duhamel, P. Jissendi, K. Dujardin, F. Auger, L. Ravasi, L. Hopes, G. Grolez, W. Firdaus, B. Sablonnière, L. Strubi-Vuillaume, N. Zahr, A. Destée, J.C. Corvol, D. Pöltl, M. Leist, C. Rose, L. Defebvre, P. Marchetti, I.Z. Cabantchik, & R. Bordet: Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21, 195-210 (2013)

65. Moreau, C., J-C. Devedjian, J. Kluza, C. Laloux, A. Jonneaux, M. Petrault, G. Ryckewaert, K. Dujardin, G. Garcon, N. Rouaix, A. Duhamel, P. Jissendi, B. Sablonniere, J-C. Corval, C. Rose, L. Defebre, P. Marchetti, I. Cabantchik, R. Bordet, & D. Devos: Targeting brain chelatable iron as a therapeutic strategy for Parkinson’s disease. Translational and clinical studies. Podium Abstract 52 BioIron London (2013)

66. Martin-Bastida, A., R.J. Ward, P. Piccini, D. Sharp, C. Kabba, M.C. Pate, R. Rexford- Newbould, M. Spino, J. Connelly, F. Tricta, R.R. Crichton, & D.T. Dexter: Brain iron chelation by deferiprone in Parkinson’s disease patients. Ann Neurol submitted (2015)

67. Crapper McLachian, DR., A.J. Dalton, T.P. Kruck, M.Y. Bell, W.L. Smith, W. Kalow, & D.F. Andrews: Intramuscular desferrioxamine in patients with Alzheimer ’s disease. Lancet 1337, 1304-08 (1991)

68. Lannfelt, L., K. Blennow, H. Zetterberg, S. Batsman, D. Ames, J. Harrison, C.L. Maters, S. Targum, A.I. Bush, R. Murdoch, J. Wilson, & C.W. Ritchie: Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7, 779-86 (2008)

69. Gilgun-Sherki, Y., E. Malamed, & D. Offen: Anti-inflammatory drugs in the treatment of neurodegenerative diseases: current state. Curr Pharm Des 12, 3509-19 (2006)

70. Ward, RJ., F. Lallemand, P. de Witte, R.R. Crichton, J. Piette, K. Tipton, K. Hemmings, A. Pitard, M. Page, L. Della Corte, D. Taylor, & D. Dexter: Anti-inflammatory actions of a taurine analogue, ethane β-sultam, in phagocytic cells, in vivo in vitro, Biochem Pharmacol 81, 743-51 (2011)
DOI: 10.1016/j.bcp.2010.12.030

71. Stefanini, C., M.A. Colivicchi, L. Della Corte, R.J. Ward, P. De Witte, F. Lallemand, K. Hemmings, A. Pitard, M.I. Page, K. Nayak, & D.T. Dexter: Ethane-β-Sultam modifies the activation of the innate immune system induced by intermittent ethanol administration in female adolescent rats J Alcohol Drug Depend 2329-6488 (2014).

72. Monk P.N., & P.J. Shaw: ALS: Life and death in a bad neighborhood. Nat Med 12, 885-887 (2006)

73. Torres-Platas S.G., S. Comeau, A. Rachalski, G.D. Bo, C. Cruceanu, G. Turecki, B Giros, & N. Mechawar: Morphometric characterization of microglial phenotypes in human cerebral cortex J Neuroinflammation 11, 12 (2014)

74. Tribl F., M. Gerlach, K. Marcus, E. Asan, T. Tatschner, T. Arzberger, H.E. Meyer, G. Bringmann, & P. Riederer: Subcellular Proteomics of Neuromelanin Granules Isolated from the Human Brain. Molecular & Cellular Proteomics 4, 945-957 (2005)

Abbreviations: PD; Parkinson’s Disease, AD-;Alzheimer’s Disease, MS;Multiple Sclerosis, FA; Friedereich Ataxia, UPDRS;Unified Parkinson’s disease rating scale, MRI;Magnetic resonance imaging, CNS, central nervous system, ROS;reactive oxygen species, Aβ; amyloid-β peptide, NFT; neurofibrillary tangles, APP; amyloid precursor protein, TLR-;Toll like receptor, COX; cyclooxygenase, LPS; lipopolysaccharide, CD;cluster of differentiation.

Key words: Iron, inflammation, Microglia Parkinson’s Disease, Alzheimer’s disease, Multiple Sclerosis, Review

Send correspondence to: Roberta J Ward, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Imperial College, London UK, Tel: 44 207 594 6665; Fax 3210456004; E-mail Roberta.Ward@imperial.ac.uk