Top

Published in:

Open Access 01-12-2012 | Review

Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Authors: Norbert Zilka, Zuzana Kazmerova, Santosh Jadhav, Peter Neradil, Aladar Madari, Dominika Obetkova, Ondrej Bugos, Michal Novak

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease.

Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM: Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 1986, 261:6084–6089.PubMed

Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986, 83:4913–4917.CrossRefPubMedPubMedCentral

Glenner GG, Wong CW: Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984, 122:1131–1135.CrossRefPubMed

Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A: Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988, 85:4506–4510.CrossRefPubMedPubMedCentral

Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA: Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988, 85:4884–4888.CrossRefPubMedPubMedCentral

Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991, 82:239–259.CrossRefPubMed

Dickson DW: Neuropathological diagnosis of Alzheimer's disease: a perspective from longitudinal clinicopathological studies. Neurobiol Aging 1997,18(4 Suppl):S21-S26.CrossRefPubMed

Iqbal K, Grundke-Iqbal I: Alzheimer's disease, a multifactorial disorder seeking multitherapies. Alzheimers Dement 2010, 6:420–424.CrossRefPubMedPubMedCentral

Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K: Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis Assoc Disord 2000, 14:47–53.CrossRef

10.

Mrak RE, Griffin WS: The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging 2001, 22:915–922.CrossRefPubMed

11.

Eikelenboom P, Veerhuis R, Scheper W, Rozemuller AJM, van Gool W, Hoozemans J: The significance of neuroinflammation in understanding Alzheimer's disease. J Neural Transm 2006, 113:1685–1695.CrossRefPubMed

12.

Walsch S, Aisen P: Inflammatory processes in Alzheimer's disease. Expert Rev Neurotherapeutics 2004, 4:793–798.CrossRef

13.

Grundke-Iqbal I, Fleming J, Tung YC, Lassmann H, Iqbal K, Joshi JG: Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neuropathol 1990, 81:105–110.CrossRefPubMed

14.

Sheffield LG, Marquis JG, Berman NE: Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimer's disease. Neurosci Lett 2000, 285:165–168.CrossRefPubMed

15.

Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P, Alafuzoff I: Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol 1999, 97:383–392.CrossRefPubMed

16.

Sheng JG, Mrak RE, Griffin WS: Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1α ⁺ microglia and S100β ⁺ astrocytes with neurofibrillary tangle stages. J Neuropathol Exp Neurol 1997, 56:285–290.CrossRefPubMed

17.

Cras P, Kawai M, Siedlak S, Perry G: Microglia are associated with the extracellular neurofibrillary tangles of Alzheimer disease. Brain Res 1991, 558:312–314.CrossRefPubMed

18.

DiPatre PL, Gelman BB: Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus. J Neuropathol Exp Neurol 1997, 56:143–149.CrossRefPubMed

19.

Probst A, Ulrich J, Heitz PU: Senile dementia of Alzheimer type: astroglial reaction to extracellular neurofibrillary tangles in the hippocampus: an immunocytochemical and electron-microscopic study. Acta Neuropathol 1982, 57:75–79.CrossRefPubMed

20.

McGeer PL, Akiyama H, Itagaki S, McGeer EG: Immune system response in Alzheimer's disease. Can J Neurol Sci 1989,16(4 Suppl):516–527.CrossRefPubMed

21.

Shen Y, Lue L, Yang L, Roher A, Kuo Y, Strohmeyer R, Goux WJ, Lee V, Johnson GV, Webster SD, Cooper NR, Bradt B, Rogers J: Complement activation by neurofibrillary tangles in Alzheimer's disease. Neurosci Lett 2001, 305:165–168.CrossRefPubMed

22.

Schwab C, Steele JC, McGeer PL: Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins. Brain Res 1996, 707:196–205.CrossRefPubMed

23.

Ishizawa K, Dickson DW: Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 2001, 60:647–657.CrossRefPubMed

24.

Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ: In vivo imaging of microglial activation with [ ¹¹ C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord 2006, 21:89–93.CrossRefPubMed

25.

Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, Brooks DJ: In vivo imaging of microglial activation with [ ¹¹ C](R)-PK11195 PET in corticobasal degeneration. Mov Disord 2004, 19:1221–1226.CrossRefPubMed

26.

Henkel K, Karitzky J, Schmid M, Mader I, Glatting G, Unger JW, Neumaier B, Ludolph AC, Reske SN, Landwehrmeyer GB: Imaging of activated microglia with PET and [ ¹¹ C]PK11195 in corticobasal degeneration. Mov Disord 2004, 19:817–821.CrossRefPubMed

27.

Paulus W, Bancher C, Jellinger K: Microglial reaction in Pick's disease. Neurosci Lett 1993, 161:89–92.CrossRefPubMed

28.

Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG: Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol 2004, 165:1643–1652.CrossRefPubMedPubMedCentral

29.

Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM: Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53:337–351.CrossRefPubMed

30.

Ikeda M, Shoji M, Kawarai T, Kawarabayashi T, Matsubara E, Murakami T, Sasaki A, Tomidokoro Y, Ikarashi Y, Kuribara H, Ishiguro K, Hasegawa M, Yen SH, Chishti MA, Harigaya Y, Abe K, Okamoto K, St George-Hyslop P, Westaway D: Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice. Am J Pathol 2005, 166:521–531.CrossRefPubMedPubMedCentral

31.

Sasaki A, Kawarabayashi T, Murakami T, Matsubara E, Ikeda M, Hagiwara H, Westaway D, George-Hyslop PS, Shoji M, Nakazato Y: Microglial activation in brain lesions with tau deposits: comparison of human tauopathies and tau transgenic mice TgTau ^P301L . Brain Res 2008, 1214:159–168.CrossRefPubMed

32.

Zilka N, Stozicka Z, Kovac A, Pilipcinec E, Bugos O, Novak M: Human misfolded truncated tau protein promotes activation of microglia and leukocyte infiltration in the transgenic rat model of tauopathy. J Neuroimmunol 2009, 209:16–25.CrossRefPubMed

33.

Stozicka Z, Zilka N, Novak P, Kovacech B, Bugos O, Novak M: Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease. J Neuroinflammation 2010, 7:64.CrossRefPubMedPubMedCentral

34.

Filipcik P, Zilka N, Bugos O, Kucerak J, Koson P, Novak P, Novak M: First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol Aging, in press. doi:10.1016/j.neurobiolaging.2010.10.015

35.

Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, Rolkova G, Kontsekova E, Novak M: Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 2006, 580:3582–3588.CrossRefPubMed

36.

Mackenzie IRA: Anti-inflammatory drugs and Alzheimer-type pathology in aging. Neurology 2000, 54:732–734.CrossRefPubMed

37.

McGeer PL, McGeer EG: NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging 2007, 28:639–647.CrossRefPubMed

38.

McGeer PL, Schulzer M, McGeer EG: Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 1996, 47:425–432.CrossRefPubMed

39.

Zandi PP, Breitner JC: Do NSAIDs prevent Alzheimer's disease? And, if so, why? The epidemiological evidence. Neurobiol Aging 2001, 22:811–817.CrossRefPubMed

40.

Aisen PS, Davis KL, Berg JD, Schafer K, Campbell K, Thomas RG, Weiner MF, Farlow MR, Sano M, Grundman M, Thal LJ: A randomized controlled trial of prednisone in Alzheimer's disease: Alzheimer's Disease Cooperative Study. Neurology 2000, 54:588–41.CrossRefPubMed

41.

Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ: Alzheimer's disease cooperative study: effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003, 289:2819–2826.CrossRefPubMed

42.

Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, Norman BA, Baranak CC: Rofecoxib protocol 091 study group: rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology 2004, 62:66–71.CrossRefPubMed

43.

de Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, Kremer B: No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial. PLoS One 2008, 3:e1475.CrossRefPubMedPubMedCentral

44.

Sonnen JA, Larson EB, Walker RL, Haneuse S, Crane PK, Gray SL, Breitner JC, Montine TJ: Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology 2010, 75:1203–1210.CrossRefPubMedPubMedCentral

45.

Beeri MS, Schmeidler J, Lesser GT, Maroukian M, West R, Leung S, Wysocki M, Perl DP, Purohit DP, Haroutunian V: Corticosteroids, but not NSAIDs, are associated with less Alzheimer neuropathology. Neurobiol Aging, in press. doi:10.1016/j.neurobiolaging.2011.02.011

46.

Streit WJ, Sammons NW, Kuhns AJ, Sparks DL: Dystrophic microglia in the aging human brain. Glia 2004, 45:208–212.CrossRefPubMed

47.

Streit WJ: Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci 2006, 29:506–510.CrossRefPubMed

48.

Streit WJ, Braak H, Xue QS, Bechmann I: Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol 2009, 118:475–485.CrossRefPubMedPubMedCentral

49.

Li Y, Liu L, Barger SW, Griffin WS: Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003, 23:1605–1611.PubMedPubMedCentral

50.

Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB: Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004, 295:245–257.CrossRefPubMed

51.

Saez TE, Pehar M, Vargas M, Barbeito L, Maccioni RB: Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons. In Vivo 2004, 18:275–280.PubMed

52.

Lee DC, Rizer J, Selenica ML, Reid P, Kraft C, Johnson A, Blair L, Gordon MN, Dickey CA, Morgan D: LPS-induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflammation 2010, 7:56.CrossRefPubMedPubMedCentral

53.

Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM: Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 2005, 25:8843–8853.CrossRefPubMed

54.

Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT: Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010, 68:19–55.CrossRefPubMedPubMedCentral

55.

Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, LaFerla FM, Callahan LM, Federoff HJ, Bowers WJ: Chronic neuron-specific tumor necrosis factor-α expression enhances the local inflammatory environment ultimately leading to neuronal death in 3 × Tg-AD mice. Am J Pathol 2008, 173:1768–1782.CrossRefPubMedPubMedCentral

56.

Gorlovoy P, Larionov S, Pham TTH, Neumann H: Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J 2009, 23:2502–2513.CrossRefPubMed

57.

Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT: CX3CR1 deficiency alters microglial activation and reduces β-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol 2010, 177:2549–2562.CrossRefPubMedPubMedCentral

58.

Ryman D, Lamb BT: Genetic and environmental modifiers of Alzheimer's disease phenotypes in the mouse. Curr Alzheimer Res 2006, 3:465–473.CrossRefPubMed

59.

Gómez-Ramos A, Díaz-Hernández M, Cuadros R, Hernández F, Avila J: Extracellular tau is toxic to neuronal cells. FEBS Lett 2006, 580:4842–4850.CrossRefPubMed

60.

Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM: In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 2011, 31:13110–13117.CrossRefPubMedPubMedCentral

61.

Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J: Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci 2008, 37:673–681.CrossRefPubMed

62.

Gómez-Ramos A, Díaz-Hernández M, Rubio A, Díaz-Hernández JI, Miras-Portugal MT, Avila J: Characteristics and consequences of muscarinic receptor activation by tau protein. Eur Neuropsychopharmacol 2009, 19:708–717.CrossRefPubMed

63.

Moe JG, Chatterjee I, Davidowitz EJ, Arancio O: Modulation of synaptic function by extracellular tau enriched in oligomers [abstract]. Alzheimers Dement 2009,5(4 Suppl):P499.CrossRef

64.

Kovac A, Zilkova M, Deli MA, Zilka N, Novak M: Human truncated tau is using a different mechanism from amyloid-β to damage the blood-brain barrier. J Alzheimers Dis 2009, 18:897–906.PubMed

65.

Kovac A, Zilka N, Kazmerova Z, Cente M, Zilkova M, Novak M: Misfolded truncated protein τ induces innate immune response via MAPK pathway. J Immunol 2011, 187:2732–2739.CrossRefPubMed

66.

Paresce DM, Ghosh RN, Maxfield FR: Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 1996, 17:553–565.CrossRefPubMed

67.

Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H: IL-4-induced selective clearance of oligomeric -amyloid peptide _1–42 by rat primary type 2 microglia. J Immunol 2008, 181:6503–6513.CrossRefPubMed

68.

Yang CN, Shiao YJ, Shie F, Guo BS, Chen PH, Cho CY, Chen YJ, Huang FL, Tsay HJ: Mechanism mediating oligomeric Aβ clearance by naïve primary microglia. Neurobiol Dis 2011, 42:221–230.CrossRefPubMed

69.

Thomas MP, Chartrand K, Reynolds A, Vitvitsky V, Banerjee R, Gendelman HE: Ion channel blockade attenuates aggregated α synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson's disease. J Neurochem 2007, 100:503–519.CrossRefPubMed

70.

Park JY, Paik SR, Jou I, Park SM: Microglial phagocytosis is enhanced by monomeric α-synuclein, not aggregated α-synuclein: implications for Parkinson's disease. Glia 2008, 56:1215–1223.CrossRefPubMed

Title: Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways
Authors: Norbert Zilka
Zuzana Kazmerova
Santosh Jadhav
Peter Neradil
Aladar Madari
Dominika Obetkova
Ondrej Bugos
Michal Novak
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-47

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Interleukin-1 participates in the classical and alternative activation of microglia/macrophages after spinal cord injury

Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results

Intravenous immunoglobulin treatment of the post-polio syndrome: sustained effects on quality of life variables and cytokine expression after one year follow up

Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation

The cytokine tumor necrosis factor-like weak inducer of apoptosis and its receptor fibroblast growth factor-inducible 14 have a neuroprotective effect in the central nervous system