Microglia function in Alzheimer's disease

Frontiers in Pharmacology

Volumn 3 FEB, Issue , 2012, Pages

  Solito, Egle ^a   Sastre, Magdalena ^b  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^b IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

Alzheimer's disease; Amyloid ; Annexin A1; Immunity; Inflammation; Microglia; Nsaids

Indexed keywords

ADVANCED GLYCATION END PRODUCT RECEPTOR; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN ANTIBODY; AMYLOID BETA PROTEIN[1-42]; ANTIINFLAMMATORY AGENT; FORMYLPEPTIDE RECEPTOR; FORMYLPEPTIDE RECEPTOR LIKE 1; IBUPROFEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDOMETACIN; INFLIXIMAB; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERLEUKIN 8; LIPOCORTIN 1; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PRESENILIN; RECOMBINANT ANNEXIN A1; SCAVENGER RECEPTOR; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

AGING; ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CELL ACTIVATION; CELL FUNCTION; CELL SURVIVAL; CYTOKINE RELEASE; CYTOKINE RESPONSE; DRUG TARGETING; EARLY DIAGNOSIS; ENCEPHALITIS; ENZYME RELEASE; HUMAN; INNATE IMMUNITY; MACROPHAGE FUNCTION; MICROGLIA; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; PROTEIN DEGRADATION; PROTEIN PROTEIN INTERACTION; SENILE PLAQUE;

EID: 84864134469     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2012.00014     Document Type: Article

References (132)

1. Akashi-Takamura, S., and Miyake, K. (2006). Toll-like receptors (TLRs) and immune disorders. J. Infect. Chemother. 12, 233-240.
2. Alafuzoff, I., Overmyer, M., Helisalmi, S., and Soininen, H. (2000). Lower counts of astroglia and activated microglia in patients with Alzheimer's disease with regular use of nonsteroidal anti-inflammatory drugs. J. Alzheimers Dis. 2, 37-46.
3. Arancio, O., Zhang, H. P., Chen, X., Lin, C., Trinchese, F., Puzzo, D., Liu, S., Hegde, A., Yan, S. F., Stern, A., Luddy, J. S., Lue, L. F., Walker, D. G., Roher, A., Buttini, M., Mucke, L., Li, W., Schmidt, A. M., Kindy, M., Hyslop, P. A., Stern, D. M., and Du Yan, S. S. (2004). RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J. 23, 4096-4105.
4. Arnaud, L., Robakis, N. K., and Figueiredo-Pereira, M. E. (2006). It may take inflammation, phospho-rylation and ubiquitination to 'tan-gle' in Alzheimer's disease. Neurode-gener. Dis. 3, 313-319.
5. Bach, J. H., Chae, H. S., Rah, J. C., Lee, M. W., Park, C. H., Choi, S. H., Choi, J. K., Lee, S. H., Kim, Y. S., Kim, K. Y., Lee, W. B., Suh, Y. H., and Kim, S. S. (2001). C-terminal frag-ment of amyloid precursor protein induces astrocytosis. J. Neurochem. 78, 109-120.
6. Bard, F., Cannon, C., Barbour, R., Burke, R. L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguyen, M., Soriano, F., Vasquez, N., Weiss, K., Welch, B., Seubert, P., Schenk, D., and Yednock, T. (2000). Peripherally administered antibod-ies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916-919.
7. Barger, S.W.,and Harmon, A. D. (1997). Microglial activation by Alzheimer amyloid precursor protein and mod-ulation by apolipoprotein E. Nature 388, 878-881.
8. Beglopoulos, V., Sun, X., Saura, C. A., Lemere, C. A., Kim, R. D., and Shen, J. (2004). Reduced b-amyloid pro-duction and increased inflammatory responses in presenilin conditional knock-out mice. J. Biol. Chem. 279, 46907-46914.
9. Benzing, W. C., Wujek, J. R., Ward, E. K., Shaffer, D., Ashe, K. H., Younkin, S. G., and Brunden, K. R. (2000). Evi-dence for glial-mediated inflamma-tion in aged APPSw transgenic mice. Neurobiol. Aging 16, 523-530.
10. Bierhaus, A., Humpert, P. M., Morcos, M., Wendt, T., Chavakis, T., Arnold, B., Stern, D. M., and Nawroth, P. P. (2005). Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. (Berl.) 83, 876-886.
11. Bonifati, D. M., and Kishore, U. (2007). Role of complement in neurodegeneration and neuroin-flammation. Mol. Immunol. 44, 999-1010.
12. Cagnin, A., Brooks, D. J., Kennedy, A. M., Gunn, R. N., Myers, R., Turkheimer, F. E., Jones, T., and Banati, R. B. (2001). In-vivo measurement of activated microglia in dementia. Lancet 358, 461-467.
13. Cameron, B., and Landreth, G. E. (2010). Inflammation, microglia, and Alzheimer's disease. Neurobiol. Dis. 37, 503-509.
14. Capurso, C., Solfrizzi, V., D'Introno, A., Colacicco, A. M., Capurso, S. A;., Capurso, A., and Panza, F. (2004). Interleukin 6-174 G/C pro-moter gene polymorphism and sporadic Alzheimer's disease: geo-graphic allele and genotype varia-tionsinEurope.Exp. Gerontol. 39, 1567-1573.
15. Carty, M.,and Bowie, A. G. (2011). Eval-uating the role of Toll-like recep-tors in diseases of the central ner-vous system. Biochem. Pharmacol. 81, 825-837.
16. Chan, W. Y., Kohsaka, S., and Rezaie, P. (2007). The origin, and cell lineage of microglia: new concepts. Brain Res. Rev. 53, 344-354.
17. Chavakis, T., Bierhaus, A., Al-Fakhri, N., Schneider, D., Witte, S., Linn, T., Nagashima, M., Morser, J., Arnold, B., Preissner, K. T., and Nawroth, P. P. (2003). The pattern recogni-tion receptor (RAGE) is a coun-terreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J. Exp. Med. 198, 1507-1515.
18. Colton, C. A. (2009). Heterogene-ity of microglial activation in the innate immune response in the brain. J. Neuroimmune Pharmacol. 4, 399-418.
19. Combs, C. K., Johnson, D. E., Karlo, J. C., Cannady, S. B., and Landreth, G. E. (2000). Inflammatory mechanisms in Alzheimer's disease: inhibition of b-amyloid stimulated proinflammatory responses and neurotoxicity by PPARg agonists. J. Neurosci. 20, 558-567.
20. Combs, C. K., Karlo, J. C., Kao, S. C., and Landreth, G. E. (2001). b-Amyloid stimulation of microglia and monocytes results in TNFa-dependent expression of inducible nitric oxide synthase and neu-ronal apoptosis. J. Neurosci. 21, 1179-1188.
21. Coraci, I. S., Husemann, J., Berman, J. W., Hulette, C., Dufour, J. H., Cam-panella, G. K., Luster, A. D., Silver-Stein, S. C., and El-Khoury, J. B. (2002). CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am. J. Pathol. 160, 101-112.
22. Cui, Y., Le, Y., Yazawa, H., Gong, W., and Wang, J. M. (2002). Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease. J. Leukoc. Biol. 72, 628-635.
23. Davoust, N., Vuaillat, C., Androdias, G., and Nataf, S. (2008). From bone marrow to microglia: barriers and avenues. Trends Immunol. 29, 227-234.
24. DeGiorgio, L. A., Shimizu, Y., Chun, H. S., Kim, Y. S., Sugama, S., Son, J. H., Joh, T. H., and Volpe, B. T. (2002). Amyloid precursor protein gene dis-ruption attenuates degeneration of substantia nigra compacta neurons following axotomy. Brain Res. 938, 38-44.
25. El Khoury, J., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., and Loike, J. D. (1996). Scav-enger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716-719.
26. Falsig, J., van Beek, J., Hermann, C., and Leist, M. (2008). Molecular basis for detection of invading pathogens in the brain. J. Neurosci. Res. 86, 1434-1447.
27. Fang, F., Lue, L. F., Yan, S., Xu, H., Luddy, J. S., Chen, D., Walker, D. G., Stern, D. M., Yan, S., Schmidt, A. M., Chen, J. X., and Yan, S. S. (2010). RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 24, 1043-1055.
28. Farfara, D., Trudler, D., Segev-Amzaleg, N., Galron, R., Stein, R., and Frenkel, D. (2011). γ-Secretase component presenilin is important for microglia β-amyloid clearance. Ann. Neurol. 69, 170-180.
29. Farina, C., Aloisi, F., and Meinl, E. (2007). Astrocytes are active players in cerebral innate immunity. Trends Immunol. 28, 138-145.
30. Fetler, L., and Amigorena, S. (2005). Neuroscience. Brain under surveil-lance: the microglia patrol. Science 309, 392-393.
31. Frautschy, S. A., Yang, F., Irrizarry, M., Hyman, B., Saido, T. C., Hsiao, K., and Cole, G. M. (1998). Microglial response to amyloid plaques in APPsw transgenic mice. Am. J. Pathol. 152, 307-317.
32. Fuhrmann, M., Bittner, T., Jung, C. K., Burgold, S., Page, R. M., Mit-teregger, G., Haass, C., Laferla, F. M., Kretzschmar, H., and Herms, J. (2010). Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat. Neurosci. 13, 411-413.
33. Gao, H. M., and Hong, J. S. (2008). Why neurodegenerative diseases are pro-gressive: uncontrolled inflammation drives disease progression. Trends Immunol. 29, 357-365.
34. Gao, H. M., Kotzbauer, P. T., Uryu, K., Leight, S., Trojanowski, J. Q., and Lee, V. M. (2008). Neuroinflam-mation and oxidation/nitration of alpha-synuclein linked to dopamin-ergic neurodegeneration. J. Neurosci. 28, 7687-7698.
35. Gelinas, D. S., DaSilva, K., Fenili, D., St George-Hyslop, P., and McLaurin, J. (2004). Immunotherapy for Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 101(Suppl. 2), 14657-14662.
36. Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kel-ley, K. W., and Johnson, R. W. (2005). Exaggerated neuroinflam-mation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 19, 1329-1331.
37. Grathwohl, S. A., Kälin, R. E., Bol-mont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., Aguzzi, A., Staufenbiel, M., Mathews, P. M., Wolburg, H., Heppner, F. L., and Jucker, M. (2009). Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361-1363.
38. Griffin, W. S., Stanley, L. C., Ling, C., White, L., MacLeod, V., Perrot, L. J., White, C. L. III, and 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.
39. Hafer-Macko, C. E., Dyck, P. J., and Koski, C. L. (2000). Complement activation in acquired and heredi-tary amyloid neuropathy. J. Peripher. Nerv. Syst. 5, 131-139.
40. Heneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Dewachter, I., Walter, J., Klockgether, T., and Van Leuven, F. (2005a). Focal glial activation coin-cides with increased BACE1 activa-tion and precedes amyloid plaque deposition in APP(V717I) trans-genic mice. J. Neuroinflammation 2, 22.
41. Heneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Kreutz, A., Dewachter, I., Kuiperi, C., Klockgether, T., Van Leuven, F., and Landreth, G. (2005b). The PPARγ agonist pioglitazone reduces inflammation and Aβ1-42 levels in APP V717I transgenic mice. Brain 128, 1442-1453.
42. Heurtaux, T., Michelucci, A., Losci-uto, S., Gallotti, C., Felten, P., Dor-ban, G., Grandbarbe, L., Morga, E., and Heuschling, P. (2010). Microglial activation depends on beta-amyloid conformation: role of the formylpeptide receptor 2. J. Neu-rochem. 114, 576-586.
43. Hickman, S. E., Allison, E. K., and El Khoury, J. (2008). Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354-8360.
44. Husemann, J., Loike, J. D., Anankov, R., Febbraio, M., and Silverstein, S. C. (2002). Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, 195-205.
45. Iribarren, P., Zhou, Y., Hu, J., Le, Y., and Wang, J. M. (2005). Role of formyl peptide receptor-like 1 (FPRL1/FPR2) in mononuclear phagocyte responses in Alzheimer disease. Immunol. Res. 31, 165-176
46. Jaworski, T., Lechat, B., Demedts, D., Gielis, L., Devijver, H., Borghgraef, P., Duimel, H., Verheyen, F., Kügler, S., and Van Leuven, F. (2011). Den-dritic degeneration, neurovascular defects, and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegenera-tion. Am. J. Pathol. 179, 2001-2015
47. Jimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., Ruano, D., Vizuete, M., Gutierrez, A., and Vitorica, J. (2008). Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial pheno-type from alternative to classic. J. Neurosci. 28, 11650-11661.
48. Kamboh, M. I., Sanghera, D. K., Fer-rell, R. E., and DeKosky, S. T. (1995). APOE*4-associated Alzheimer's dis-ease risk is modified by alpha 1-antichymotrypsin polymorphism. Nat. Genet. 10, 486-488.
49. Keene, C. D., Cudaback, E., Li, X., Montine, K. S., and Montine, T. J. (2011). Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr. Opin. Neurobiol. 21, 920-928.
50. Knapp, M., and Prince, M. (2007). Dementia UK the Full Report.Lon-don: Alzheimer's Society. Kofler, J., and Wiley, C. A. (2011). Microglia: key innate immune cells of the brain. Toxicol. Pathol. 39, 103-114.
51. Kreutzberg, G. W. (1996). Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312-318
52. Le, Y., Gong, W., Tiffany, H.L., Tumanov, A., Nedospasov, S., Shen, W., Dun-lop, N. M., Gao, J. L., Murphy, P. M., Oppenheim, J. J., and Wang, J. M. (2001). Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J. Neurosci. 21, RC123.
53. Le, Y., Murphy, P. M., and Wang, J. M. (2002). Formyl-peptide recep-tors revisited. Trends Immunol. 23, 541-548.
54. Lehmann, J. M., Lenhard, J. M., Oliver, B. B., Ringold, G. M., and Kliewer, S. A. (1997). Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 272, 3406-3410.
55. Lehnardt, S. (2010). Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58, 253-263.
56. Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J., and Vartanian, T. (2003). Activation of innate immu-nity in the CNS triggers neurode-generation through a Toll-like recep-tor 4-dependent pathway. Proc. Natl. Acad. Sci. U.S.A. 100, 8514-8519.
57. Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., Tran, T., Ubeda, O., Ashe, K. H., Frautschy, S. A., and Cole, G. M. (2000). Ibupro-fen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J. Neurosci. 20, 5709-5714.
58. Liu, B., and Hong, J.-S. (2003). Role of microglia in inflammation-mediated neurodegenerative dis-eases: mechanisms and strategies for therapeutic intervention. J. Pharma-col. Exp. Ther. 304, 1-7.
59. Lleo, A., Galea, E.,and Sastre, M. (2007). Molecular targets of non-steroidal anti-inflammatory drugs in neu-rodegenerative diseases. Cell. Mol. Life Sci. 64, 1403-1418.
60. Lue, L. F., Kuo, Y. M., Beach, T., and Walker, D. G. (2010). Microglia acti-vation and anti-inflammatory reg-ulation in Alzheimer's disease. Mol. Neurobiol. 41, 115-128.
61. Lue, L. F., Walker, D. G., Brachova, L., Beach, T. G., Rogers, J., Schmidt, A. M., Stern, D. M., and Yan, S. D. (2001). Involvement of microglial receptor for advanced glycation end-products (RAGE) inAlzheimer's dis-ease: identification of a cellular acti-vation mechanism. Exp. Neurol. 171, 29-45.
62. Mackenzie, I. R., and Muñoz, D. G. (1998). Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology 50, 986-990.
63. Maeda, J., Zhang, M. R., Okauchi, T., Ji, B., Ono, M., Hattori, S., Kumata, K., Iwata, N., Saido, T. C., Trojanowski, J. Q., Lee, V. M., Staufenbiel, M., Tomiyama, T., Mori, H., Fukumura, T., Suhara, T and Higuchi, M. (2011). In vivo positron emission tomo-graphic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders. J. Neurosci. 31, 4720-4730.
64. Mandrekar, S., Jiang, Q., Lee, C. Y., Koenigsknecht-Talboo, J., Holtzman, D. M., and Landreth, G. E. (2009). Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J. Neurosci. 29, 4252-4262.
65. Maragakis, N. J., and Rothstein, J. D. (2006). Mechanisms of disease: astrocytes in neurodegenerative dis-ease. Nat. Clin. Pract. Neurol. 2, 679-689.
66. Matsuoka, Y., Picciano, M., Malester, B., LaFrancois, J., Zehr, C., Daeschner, J. M., Olschowka, J. A., Fonseca, M. I., O'Banion, M. K., Tenner, A. J., Lemer, C. A., and Duff, K. (2001). Inflammatory responses to amyloi-dosis in a transgenic mouse model of Alzheimer's disease. Am. J. Pathol. 158, 1345-1354.
67. McArthur, S., Cristante, E., Paterno, M., Christian, H., Roncaroli, F., Gillies, G. E., and Solito, E. (2010). Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J. Immunol. 185, 6317-6328.
68. McColl, B. W., Rothwell, N. J.,and Allan, S. M. (2007). Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1-and neutrophil-dependent mechanisms. J. Neurosci. 27, 4403-4412.
69. McCusker, S. M., Curran, M. D., Dynan, K. B., McCullagh, C. D., Urquhart, D. D., Middleton, D., Patterson, C. C., McIlroy, S. P., and Passmore, A. P. (2001). Association between poly-morphism in regulatory region of gene encoding tumour necrosis fac-tor alpha and risk of Alzheimer's dis-ease and vascular dementia: a case-control study. Lancet 357, 436-439
70. McGeer, P. L., and McGeer, E. G. (1998). Mechanisms of cell death in Alzheimer disease-immunopathol-ogy. J. Neural Transm. Suppl. 54, 159-166.
71. Miyake, K. (2007). Innate immune sens-ing of pathogens and danger signals by cell surface toll-like receptors. Semin. Immunol. 19, 3-10.
72. Mrak, R. E., and Griffin, W. S. T. (2005). Glia and their cytokines in progres-sion of neurodegeneration. Neuro-biol. Aging 26, 349-354.
73. Napoli, I., and Neumann, H. (2009). Microglial clearance function in health and disease. Neuroscience 158, 1030-1038.
74. Neher, J. J., Neniskyte, U., Zhao, J. W., Bal-Price, A., Tolkovsky, A. M., and Brown, G. C. (2011). Inhibi-tion of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J. Immunol. 186, 4973-4983.
75. Neumann, H., Kotter, M. R., and Franklin, R. J. (2009). Debris clear-ance by microglia: an essential link between degeneration and regenera-tion. Brain 132, 288-295.
76. Nguyen, M. D., D'Aigle, T., Gowing, G., Julien, J. P., and Rivest, S. (2004). Exacerbation of motor neuron dis-ease by chronic stimulation of innate immunity in a mouse model of amy-otrophic lateral sclerosis. J. Neurosci. 24, 1340-1349.
77. Nicoll, J. A., Mrak, R. E., Graham, D. I., Stewart, J., Wilcock, G., Mac-Gowan, S., Esiri, M. M., Murray, L. S., Dewar, D., Love, S., Moss, T., and Griffin, W. S. (2000). Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann. Neu-rol. 47, 365-368.
78. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318.
79. Njie, E. G., Boelen, E., Stassen, F. R., Steinbusch, H. W., Borchelt, D. R., and Streit, W. J. (2012). Ex vivo cul-tures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neu-robiol. Aging 33, 195.e1-195.e12.
80. Okello, A., Edison, P., Archer, H. A., Turkheimer, F. E., Kennedy, J., Bul-lock, R., Walker, Z., Kennedy, A., Fox, N., Rossor, M., and Brooks, D. J. (2009). Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology 72, 56-62.
81. Ouchi, Y., Yoshikawa, E., Sekine, Y., Futatsubashi, M., Kanno, T., Ogusu, T., and Torizuka, T. (2005). Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann. Neurol. 57, 168-175.
82. Pan, X. D., Zhu, Y. G., Lin, N., Zhang, J., Ye, Q. Y., Huang, H. P., and Chen, X. C. (2011). Microglial phagocytosis induced by fibril-lar beta-amyloid is attenuated by oligomeric beta-amyloid: implica-tions for Alzheimer's disease. Mol. Neurodegener. 6, 45.
83. Pancer, Z., and Cooper, M. D. (2006). The evolution of adaptive immunity. Annu. Rev. Immunol. 24, 497-518.
84. Paresce, D. M., Ghosh, R. N., and Maxfield, F. R. (1996). Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 17, 553-565.
85. Permanne, B., Adessi, C., Saborio, G. P., Fraga, S., Frossard, M. J., Van Dorpe, J., Dewachter, I., Banks, W. A., Van Leuven, F., and Soto, C. (2002). Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a b-sheet breaker peptide. FASEB J. 16, 860-862.
86. Perretti, M., and D'Acquisto, F. (2009). Annexin A1 and glucocorticoids as effectors of the resolution of inflam-mation. Nat. Rev. Immunol. 9,62-70
87. Perry, R. T., Collins, J. S., Wiener, H., Acton, R., and Go, R. C. P. (2001). The role of TNF and its receptors in Alzheimer's disease. Neurobiol. Aging 22, 873-883.
88. Perry, V. H. (2004). The influence of systemic inflammation on inflam-mation in the brain: implications for chronic neurodegenerative disease. Brain Behav. Immun. 18, 407-413.
89. Perry, V. H.,andAndersson, P. B. (1992). The inflammatory response in the CNS. Neuropathol. Appl. Neurobiol. 18, 454-459.
90. Perry, V. H., Anthony, D. C., Bell, M. D., Lawson, L. J., Reid, D. M., and Gordon, S. (1996). Microglia activa-tion and inflammation in the CNS. J. Neurochem. 66, S70.
91. Perry, V. H., Cunningham, C., and Holmes, C. (2007). Systemic infec-tions and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161-167.
92. Perry, V. H., Matyszak, M. K., and Fearn, S. (1993). Altered antigen expression of microglia in the aged rodent CNS. Glia 7, 60-67.
93. Perry, V. H., Nicoll, J. A., and Holmes, C. (2010). Microglia in neurodegen-erative disease. Nat. Rev. Neurol. 6, 193-201.
94. Polazzi, E., and Monti, B. (2010). Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog. Neurobiol. 92, 293-315.
95. Qiu, W. Q., Walsh, D. M., Ye, Z., Vekrel-lis, K., Zhang, J., Podlisny, M. B., Rosner, M. R., Safavi, A., Hersh, L. B., and Selkoe, D. J. (1998). Insulin-degrading enzyme regulates extra-cellular levels of amyloid b-protein by degradation. J. Biol. Chem. 273, 32730-32738.
96. Qiu, W. Q., Ye, Z., Kholodenko, D., Seu-bert, P., and Selkoe, D. J. (1997). Degradation of amyloid b-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J. Biol. Chem. 272, 6641-6646.
97. Ransohoff, R. M., and Perry, V. H. (2009). Microglial physiol-ogy: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145.
98. Reed-Geaghan, E. G., Savage, J. C., Hise, A. G., and Landreth, G. E. (2009). CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J. Neurosci. 29, 11982-11992.
99. Richard, K. L., Filali, M., Préfontaine, P., and Rivest, S. (2008). Toll-like recep-tor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J. Neurosci. 28, 5784-5793.
100. Rivest, S. (2003). Molecular insights on the cerebral innate immune system. Brain Behav. Immun. 17, 13-19.
101. Rivest, S. (2009). Regulation of innate immune responses in the brain. Nat. Rev. Immunol. 9, 429-439.
102. Roberts, J. C., Friel, S. L., Roman, S., Perren, M., Harper, A., Davis, J. B., Richardson, J. C., Virley, D., and Medhurst, A. D. (2009). Autoradi-ographical imaging of PPARgamma agonist effects on PBR/TSPO bind-ing in TASTPM mice. Exp. Neurol. 216, 459-470.
103. Rogers, J., Mastroeni, D., Leonard, B., Joyce, J., and Grover, A. (2007). Neu-roinflammation in Alzheimer's dis-ease and Parkinson's disease: are microglia pathogenic in either disor-der? Int. Rev. Neurobiol. 82, 235-246
104. Salminen, A., Ojala, J., Kauppinen, A., Kaarniranta, K., and Suuro-nen, T. (2009). Inflammation in Alzheimer's disease: amyloid-beta oligomers trigger innate immu-nity defence via pattern recogni-tion receptors. Prog. Neurobiol. 87, 181-194.
105. Sastre, M., and Gentleman, S. M. (2010). NSAIDs: how they work and their prospects as therapeutics in Alzheimer's dis-ease. Front. Aging Neurosci. 2:20. doi:10.3389/fnagi.2010.00020
106. Sastre, M., Klockgether, T., and Heneka, M. T. (2006a). Contri-bution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int. J. Dev. Neurosci. 24, 167-176.
107. Sastre, M., Roßner, S., Bogdanovic, N., Rosen, E., Dewachter, I., Thal, D., Evert, B., Klockgether, T., van Leuven, F., and Heneka, M. T. (2006b). Non-steroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc. Natl. Acad. Sci. U.S.A. 103, 443-448
108. Sastre, M., Richardson, J., Gentleman, S. M., and Brooks, D. (2011). Inflam-matory risk factors and patholo-gies associated with Alzheimer's disease. Curr. Alzheimer Res. 8, 132-141.
109. Sastre, M., Walter, J., and Gentleman, S. M. (2008). Interactions between APP secretases and inflammatory mediators. J. Neuroinflammation 5, 25.
110. Schmidt, A. M., Yan, S. D., Yan, S. F., and Stern, D. M. (2001). The multiligand receptor RAGE as a progression fac-tor amplifying immune and inflam-matory responses. J. Clin. Invest. 108, 949-955.
111. Schwartz, M., and Shechter, R. (2010). Systemic inflammatory cells fight off neurodegenerative disease. Nat. Rev. Neurol. 6, 405-410.
112. Shen, Y., and Meri, S. (2003). Yin and Yang: complement activation and regulation in Alzheimer's disease. Prog. Neurobiol. 70, 463-472.
113. Shi, J. Q., Shen, W., Chen, J., Wang, B. R., Zhong, L. L., Zhu, Y. W., Zhu, H. Q., Zhang, Q. Q., Zhang, Y. D., and Xu, J. (2011). Anti-TNF-α reduces amyloid plaques and tau phospho-rylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res. 1368, 239-247.
114. Sierra, A., Gottfried-Blackmore, A. C., McEwen, B. S., and Bulloch, K. (2007). Microglia derived from aging mice exhibit an altered inflam-matory profile. Glia 55, 412-424.
115. Solito, E., McArthur, S., Christian, H., Gavins, F., Buckingham, J. C., and Gillies, G. E. (2008). Annexin A1 in the brain-undiscovered roles? Trends Pharmacol. Sci. 29, 135-142.
116. Streit, W., Braak, H., Xue, Q. S., and Bechmann, I. (2009). Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 118, 475-485.
117. Streit, W. J., Miller, K. R., Lopes, K. O., and Njie, E. (2008). Microglial degeneration in the aging brain-bad news for neurons? Front. Biosci. 13, 3423-3438.
118. Streit, W. J., Sammons, N. W., Kuhns, A. J., and Sparks, D. L. (2004). Dystrophic microglia in the aging human brain. Glia 45, 208-212.
119. Sy, M., Kitazawa, M., Medeiros, R., Whitman, L., Cheng, D., Lane, T. E., and Laferla, F. M. (2011). Inflam-mation induced by infection poten-tiates tau pathological features in transgenic mice. Am. J. Pathol. 178, 2811-2822.
120. Tahara, K., Kim, H. D., Jin, J. J., Maxwell, J. A., Li, L., and Fukuchi, K. (2006). Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129, 3006-3019.
121. Walter, S., Letiembre, M., Liu, Y., Heine, H., Penke, B., Hao, W., Bode, B., Manietta, N., Walter, J., Schulz-Schuffer, W., and Fass-bender, K. (2007). Role of the toll-like receptor 4 in neuroin-flammation in Alzheimer's dis-ease. Cell. Physiol. Biochem. 20, 947-956.
122. Weiner, H. L., and Selkoe, D. J. (2002). Inflammation and therapeutic vac-cination in CNS diseases. Nature 420, 879-884.
123. Weller, C., Oxlade, N., Dobbs, S. M., Dobbs, R. J., Charlett, A., and Bjarnason, I. T. (2005). Role of inflammation in gastrointesti-nal tract in aetiology and patho-genesis of idiopathic parkinsonism. FEMS Immunol. Med. Microbiol. 44, 129-135.
124. Willson, T. M., Brown, P. J., Sternbach, D. D., and Henke, B. R. (2000). The PPARs: from orphan receptors to drug discovery. J. Med. Chem. 43, 527-550.
125. Wyss-Coray, T. (2006). Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med. 12, 1005-1015.
126. Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F., Silverstein, S. C., Husemann, J. (2003). Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat. Med. 9, 453-457.
127. Xie, Z., Morgan, T. E., Rozovsky, I., and Finch, C. E. (2003). Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp. Neurol. 182, 135-141.
128. Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D., and Schmidt, A. M. (1996). RAGE and amyloid-beta peptide neurotox-icity in Alzheimer's disease. Nature 382, 685-691.
129. Yang, M. S., Ji, K. A., Jeon, S. B., Jin, B. K., Kim, S. U., Jou, I., and Joe, E. (2006). Interleukin-13 enhances cyclooxygenase-2 expres-sion in activated rat brain microglia: implications for death of acti-vated microglia. J. Immunol. 177, 1323-1329.
130. Ye, S. M., and Johnson, R. W. (1999). Increased interleukin-6 expression by microglia from brain of aged mice. J. Neuroimmunol. 93, 139-148.
131. Yong, V.W.,and Rivest, S. (2009). Taking advantage of the systemic immune system to cure brain diseases. Neuron 64, 55-60.
132. Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S. M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Tro-janowski, J. Q.,and Lee, V. M. (2007). Synapse loss and microglial acti-vation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-351.