Innate immunity in Alzheimer's disease: A complex affair

CNS and Neurological Disorders - Drug Targets

Volumn 12, Issue 5, 2013, Pages 593-607

  Guillot Sestier, Marie Victoire ^a   Town, Terrence ^a,b,c  

^a CEDARS SINAI MEDICAL CENTER   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Alzheimer disease; Amyloid ; Chemokine; Cytokine; Gliosis; Inflammation; Innate immunity; Microglia; Neuroinflammation; Peptide; Phagocytosis

Indexed keywords

ADVANCED GLYCATION END PRODUCT; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; CD36 ANTIGEN; CD37 ANTIGEN; CD40 ANTIGEN; CD45 ANTIGEN; CHEMOKINE RECEPTOR CX3CR1; CHEMOKINE RECEPTOR CXCR2; CHEMOKINE RECEPTOR CXCR3; CXCL2 CHEMOKINE; FRACTALKINE; GELATINASE B; INFLAMMASOME; INSULINASE; INTERLEUKIN 1BETA; INTERLEUKIN 8; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; MEMBRANE METALLOENDOPEPTIDASE; NUCLEOTIDE BINDING OLIGOMERIZATION DOMAIN LIKE RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PROTEIN BAX; PROTEIN S 100; RANTES; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VERY LATE ACTIVATION ANTIGEN 6;

ALZHEIMER DISEASE; AMNESIA; AMYLOID PLAQUE; AMYLOIDOSIS; ARTICLE; CELL ACTIVATION; CELL PHAGOCYTOSIS; DISEASE COURSE; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; LEARNING; MENINGOENCEPHALITIS; MICROGLIA; MILD COGNITIVE IMPAIRMENT; NERVE CELL LESION; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; OXIDATIVE STRESS; PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; SIGNAL TRANSDUCTION;

EID: 84882751308     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/1871527311312050008     Document Type: Article

References (197)

1. Blümcke, I. History of Neuroscience: Alois Alzheimer's First Report on Cortical neurodegeneration. IBRO History Neurosci., 2003.
2. Perlmutter, L.S.; Barron, E.; Chui, H.C. Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease. Neurosci. Lett., 1990, 119(1), 32-36.
3. McGeer, P.L.; Itagaki, S.; Tago, H.; McGeer, E.G. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci. Lett., 1987, 79(1-2), 195-200.
4. Dickson, D.W.; Farlo, J.; Davies, P.; Crystal, H.; Fuld, P.; Yen, S.H. Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. Am. J. Pathol., 1988, 132(1), 86-101.
5. Arends, Y.M.; Duyckaerts, C.; Rozemuller, J.M.; Eikelenboom, P.; Hauw, J.J. Microglia, amyloid and dementia in alzheimer disease. A correlative study. Neurobiol. Aging, 2000, 21(1), 39-47.
6. Cagnin, A.; Kassiou, M.; Meikle, S.R.; Banati, R.B. In vivo evidence for microglial activation in neurodegenerative dementia. Acta Neurol. Scand. Suppl., 2006, 185, 107-114.
7. Okello, A.; Edison, P.; Archer, H.A.; Turkheimer, F.E.; Kennedy, J.; Bullock, R.; Walker, Z.; Kennedy, A.; Fox, N.; Rossor, M.; Brooks, D.J. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology, 2009, 72(1), 56-62.
8. Vehmas, A.K.; Kawas, C.H.; Stewart, W.F.; Troncoso, J.C. Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol. Aging, 2003, 24(2), 321-331.
9. Bornemann, K.D.; Wiederhold, K.H.; Pauli, C.; Ermini, F.; Stalder, M.; Schnell, L.; Sommer, B.; Jucker, M.; Staufenbiel, M. Abetainduced inflammatory processes in microglia cells of APP23 transgenic mice. Am. J. Pathol., 2001, 158(1), 63-73.
10. Bolmont, T.; Haiss, F.; Eicke, D.; Radde, R.; Mathis, C.A.; Klunk, W.E.; Kohsaka, S.; Jucker, M.; Calhoun, M.E. Dynamics of the 602 CNS & Neurological Disorders -Drug Targets, 2013, Vol. 12, No. 5 Guillot-Sestier and Town microglial/amyloid interaction indicate a role in plaque maintenance. J. Neurosci., 2008, 28(16), 4283-4292.
11. Graeber, M.B.; Streit, W.J. Microglia: biology and pathology. Acta Neuropathol., 2010, 119(1), 89-105.
12. Boddeke, E.W.; Meigel, I.; Frentzel, S.; Gourmala, N.G.; Harrison, J.K.; Buttini, M.; Spleiss, O.; Gebicke-Harter, P. Cultured rat microglia express functional beta-chemokine receptors. J. Neuroimmunol., 1999, 98(2), 176-184.
13. Van Coillie, E.; Van Damme, J.; Opdenakker, G. The MCP/eotaxin subfamily of CC chemokines. Cytokine Growth Factor Rev., 1999, 10(1), 61-86.
14. El Khoury, J.B.; Moore, K.J.; Means, T.K.; Leung, J.; Terada, K.; Toft, M.; Freeman, M.W.; Luster, A.D. CD36 mediates the innate host response to beta-amyloid. J. Exp. Med., 2003, 197(12), 1657-1666.
15. Prat, E.; Baron, P.; Meda, L.; Scarpini, E.; Galimberti, D.; Ardolino, G.; Catania, A.; Scarlato, G. The human astrocytoma cell line U373MG produces monocyte chemotactic protein (MCP)-1 upon stimulation with beta-amyloid protein. Neurosci. Lett., 2000, 283(3), 177-180.
16. Johnstone, M.; Gearing, A.J.; Miller, K.M. A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J. Neuroimmunol., 1999, 93(1-2), 182-193.
17. Oddo, S.; Caccamo, A.; Shepherd, J.D.; Murphy, M.P.; Golde, T.E.; Kayed, R.; Metherate, R.; Mattson, M.P.; Akbari, Y.; LaFerla, F.M. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 2003, 39(3), 409-421.
18. Janelsins, M.C.; Mastrangelo, M.A.; Oddo, S.; LaFerla, F.M.; Federoff, H.J.; Bowers, W.J. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J. Neuroinflammation, 2005, 2, 23.
19. Jankowsky, J.L.; Fadale, D.J.; Anderson, J.; Xu, G.M.; Gonzales, V.; Jenkins, N.A.; Copeland, N.G.; Lee, M.K.; Younkin, L.H.; Wagner, S.L.; Younkin, S.G.; Borchelt, D.R. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet., 2004, 13(2), 159-170.
20. Ishizuka, K.; Kimura, T.; Igata-yi, R.; Katsuragi, S.; Takamatsu, J.; Miyakawa, T. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer's disease. Psychiatry Clin. Neurosci., 1997, 51(3), 135-138.
21. El Khoury, J.; Toft, M.; Hickman, S.E.; Means, T.K.; Terada, K.; Geula, C.; Luster, A.D. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med., 2007, 13(4), 432-438.
22. Hsiao, K.; Chapman, P.; Nilsen, S.; Eckman, C.; Harigaya, Y.; Younkin, S.; Yang, F.; Cole, G. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 1996, 274(5284), 99-102.
23. Nishiyori, A.; Minami, M.; Ohtani, Y.; Takami, S.; Yamamoto, J.; Kawaguchi, N.; Kume, T.; Akaike, A.; Satoh, M. Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia? FEBS Lett., 1998, 429(2), 167-172.
24. Harrison, J.K.; Jiang, Y.; Chen, S.; Xia, Y.; Maciejewski, D.; McNamara, R.K.; Streit, W.J.; Salafranca, M.N.; Adhikari, S.; Thompson, D.A.; Botti, P.; Bacon, K.B.; Feng, L. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA, 1998, 95(18), 10896-10901.
25. Lehman, E.J.; Kulnane, L.S.; Lamb, B.T. Alterations in betaamyloid production and deposition in brain regions of two transgenic models. Neurobiol. Aging, 2003, 24(5), 645-653.
26. Lee, S.; Varvel, N.H.; Konerth, M.E.; Xu, G.; Cardona, A.E.; Ransohoff, R.M.; Lamb, B.T. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am. J. Pathol., 2010, 177(5), 2549-2562.
27. Kurt, M.A.; Davies, D.C.; Kidd, M.; Duff, K.; Rolph, S.C.; Jennings, K.H.; Howlett, D.R. Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Exp. Neurol., 2001, 171(1), 59-71.
28. Fuhrmann, M.; Bittner, T.; Jung, C.K.; Burgold, S.; Page, R.M.; Mitteregger, G.; Haass, C.; LaFerla, F.M.; Kretzschmar, H.; Herms, J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat. Neurosci., 2010, 13(4), 411-413.
29. Patel, N.S.; Paris, D.; Mathura, V.; Quadros, A.N.; Crawford, F.C.; Mullan, M.J. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. J. Neuroinflammation, 2005, 2(1), 9.
30. Lue, L.F.; Rydel, R.; Brigham, E.F.; Yang, L.B.; Hampel, H.; Murphy, G.M., Jr.; Brachova, L.; Yan, S.D.; Walker, D.G.; Shen, Y.; Rogers, J. Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia, 2001, 35(1), 72-79.
31. Raivich, G.; Moreno-Flores, M.T.; Moller, J.C.; Kreutzberg, G.W. Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse. Eur. J. Neurosci., 1994, 6(10), 1615-1618.
32. Streit, W.J.; Hurley, S.D.; McGraw, T.S.; Semple-Rowland, S.L. Comparative evaluation of cytokine profiles and reactive gliosis supports a critical role for interleukin-6 in neuron-glia signaling during regeneration. J. Neurosci. Res., 2000, 61(1), 10-20.
33. Mizuno, T.; Doi, Y.; Mizoguchi, H.; Jin, S.; Noda, M.; Sonobe, Y.; Takeuchi, H.; Suzumura, A. Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am. J. Pathol., 2011, 179(4), 2016-2027.
34. Laske, C.; Stransky, E.; Hoffmann, N.; Maetzler, W.; Straten, G.; Eschweiler, G.W.; Leyhe, T. Macrophage colony-stimulating factor (M-CSF) in plasma and CSF of patients with mild cognitive impairment and Alzheimer's disease. Curr. Alzheimer Res., 2010, 7(5), 409-414.
35. Krieger, M.; Herz, J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu. Rev. Biochem., 1994, 63, 601-637.
36. El Khoury, J.; Hickman, S.E.; Thomas, C.A.; Cao, L.; Silverstein, S.C.; Loike, J.D. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature, 1996, 382(6593), 716-719.
37. Paresce, D.M.; Ghosh, R.N.; Maxfield, F.R. Microglial cells internalize aggregates of the Alzheimer's disease amyloid betaprotein via a scavenger receptor. Neuron, 1996, 17(3), 553-565.
38. Husemann, J.; Loike, J.D.; Anankov, R.; Febbraio, M.; Silverstein, S.C. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia, 2002, 40(2), 195-205.
39. Chung, H.; Brazil, M.I.; Irizarry, M.C.; Hyman, B.T.; Maxfield, F.R. Uptake of fibrillar beta-amyloid by microglia isolated from MSR-A (type I and type II) knockout mice. Neuroreport, 2001, 12(6), 1151-1154.
40. Coraci, I.S.; Husemann, J.; Berman, J.W.; Hulette, C.; Dufour, J.H.; Campanella, G.K.; Luster, A.D.; Silverstein, S.C.; El-Khoury, J.B. 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., 2002, 160(1), 101-112.
41. Bamberger, M.E.; Harris, M.E.; McDonald, D.R.; Husemann, J.; Landreth, G.E. A cell surface receptor complex for fibrillar betaamyloid mediates microglial activation. J. Neurosci., 2003, 23(7), 2665-2674.
42. 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.; Schmidt, A.M. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature, 1996, 382(6593), 685-691.
43. Alarcon, R.; Fuenzalida, C.; Santibanez, M.; von Bernhardi, R. Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surfacebound beta-amyloid. J. Biol. Chem., 2005, 280(34), 30406-30415.
44. Marzolo, M.P.; von Bernhardi, R.; Bu, G.; Inestrosa, N.C. Expression of alpha(2)-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) in rat microglial cells. J. Neurosci. Res., 2000, 60(3), 401-411.
45. Narita, M.; Holtzman, D.M.; Schwartz, A.L.; Bu, G. Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J. Neurochem., 1997, 69(5), 1904-1911.
46. Han, J.; Ulevitch, R.J. Limiting inflammatory responses during activation of innate immunity. Nat. Immunol., 2005, 6(12), 1198-1205.
47. Letiembre, M.; Liu, Y.; Walter, S.; Hao, W.; Pfander, T.; Wrede, A.; Schulz-Schaeffer, W.; Fassbender, K. Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol. Aging, 2009, 30(5), 759-768.
48. Liu, Y.; Walter, S.; Stagi, M.; Cherny, D.; Letiembre, M.; Schulz-Schaeffer, W.; Heine, H.; Penke, B.; Neumann, H.; Fassbender, K.; LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain, 2005, 128(Pt 8), 1778-1789.
49. Walter, S.; Letiembre, M.; Liu, Y.; Heine, H.; Penke, B.; Hao, W.; Bode, B.; Manietta, N.; Walter, J.; Schulz-Schuffer, W.; Fassbender, K. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol. Biochem., 2007, 20(6), 947-956.
50. Fassbender, K.; Walter, S.; Kuhl, S.; Landmann, R.; Ishii, K.; Bertsch, T.; Stalder, A.K.; Muehlhauser, F.; Liu, Y.; Ulmer, A.J.; Rivest, S.; Lentschat, A.; Gulbins, E.; Jucker, M.; Staufenbiel, M.; Brechtel, K.; Walter, J.; Multhaup, G.; Penke, B.; Adachi, Y.; Hartmann, T.; Beyreuther, K. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J., 2004, 18(1), 203-205.
51. Bsibsi, M.; Ravid, R.; Gveric, D.; van Noort, J.M. Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol., 2002, 61(11), 1013-1021.
52. Richard, K.L.; Filali, M.; Prefontaine, P.; Rivest, S. Toll-like receptor 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., 2008, 28(22), 5784-5793.
53. Jin, J.J.; Kim, H.D.; Maxwell, J.A.; Li, L.; Fukuchi, K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J. Neuroinflammation, 2008, 5, 23.
54. Udan, M.L.; Ajit, D.; Crouse, N.R.; Nichols, M.R. Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. J. Neurochem., 2008, 104(2), 524-533.
55. Jana, M.; Palencia, C.A.; Pahan, K. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J. Immunol., 2008, 181(10), 7254-7262.
56. Reed-Geaghan, E.G.; Reed, Q.W.; Cramer, P.E.; Landreth, G.E. Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu. J. Neurosci., 2010, 30(46), 15369-15373.
57. Minoretti, P.; Gazzaruso, C.; Vito, C.D.; Emanuele, E.; Bianchi, M.; Coen, E.; Reino, M.; Geroldi, D. Effect of the functional tolllike receptor 4 Asp299Gly polymorphism on susceptibility to lateonset Alzheimer's disease. Neurosci. Lett., 2006, 391(3), 147-149.
58. Rodriguez-Rodriguez, E.; Sanchez-Juan, P.; Mateo, I.; Infante, J.; Sanchez-Quintana, C.; Garcia-Gorostiaga, I.; Berciano, J.; Combarros, O. Interaction between CD14 and LXRbeta genes modulates Alzheimer's disease risk. J. Neurol. Sci., 2008, 264(1-2), 97-99.
59. McGeer, P.L.; McGeer, E.G. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Brain Res. Rev., 1995, 21(2), 195-218.
60. Togo, T.; Akiyama, H.; Kondo, H.; Ikeda, K.; Kato, M.; Iseki, E.; Kosaka, K. Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases. Brain Res., 2000, 885(1), 117-121.
61. Calingasan, N.Y.; Erdely, H.A.; Altar, C.A. Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol. Aging, 2002, 23(1), 31-39.
62. Tan, J.; Town, T.; Paris, D.; Mori, T.; Suo, Z.; Crawford, F.; Mattson, M.P.; Flavell, R.A.; Mullan, M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science, 1999, 286(5448), 2352-2355.
63. Wang, T.; Town, T.; Alexopoulou, L.; Anderson, J.F.; Fikrig, E.; Flavell, R.A. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat. Med., 2004, 10(12), 1366-1373.
64. Townsend, K.P.; Town, T.; Mori, T.; Lue, L.F.; Shytle, D.; Sanberg, P.R.; Morgan, D.; Fernandez, F.; Flavell, R.A.; Tan, J. CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide. Eur. J. Immunol., 2005, 35(3), 901-910.
65. Tan, J.; Town, T.; Crawford, F.; Mori, T.; DelleDonne, A.; Crescentini, R.; Obregon, D.; Flavell, R.A.; Mullan, M.J. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat. Neurosci., 2002, 5(12), 1288-1293.
66. Tan, J.; Town, T.; Mori, T.; Wu, Y.; Saxe, M.; Crawford, F.; Mullan, M. CD45 opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activated protein kinase. J. Neurosci., 2000, 20(20), 7587-7594.
67. Tan, J.; Town, T.; Mullan, M. CD45 inhibits CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK pathway. J. Biol. Chem., 2000, 275(47), 37224-37231.
68. Zhu, Y.; Hou, H.; Rezai-Zadeh, K.; Giunta, B.; Ruscin, A.; Gemma, C.; Jin, J.; Dragicevic, N.; Bradshaw, P.; Rasool, S.; Glabe, C.G.; Ehrhart, J.; Bickford, P.; Mori, T.; Obregon, D.; Town, T.; Tan, J. CD45 deficiency drives amyloid-beta peptide oligomers and neuronal loss in Alzheimer's disease mice. J. Neurosci., 2011, 31(4), 1355-1365.
69. Masliah, E.; Mallory, M.; Hansen, L.; Alford, M.; Albright, T.; Terry, R.; Shapiro, P.; Sundsmo, M.; Saitoh, T. Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer's disease. Acta Neuropathol., 1991, 83(1), 12-20.
70. Shimada, K.; Crother, T.R.; Karlin, J.; Dagvadorj, J.; Chiba, N.; Chen, S.; Ramanujan, V.K.; Wolf, A.J.; Vergnes, L.; Ojcius, D.M.; Rentsendorj, A.; Vargas, M.; Guerrero, C.; Wang, Y.; Fitzgerald, K.A.; Underhill, D.M.; Town, T.; Arditi, M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 2012, 36(3), 401-414.
71. Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol., 2008, 9(8), 857-865.
72. Davalos, D.; Grutzendler, J.; Yang, G.; Kim, J.V.; Zuo, Y.; Jung, S.; Littman, D.R.; Dustin, M.L.; Gan, W.B. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci., 2005, 8(6), 752-758.
73. Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 2005, 308(5726), 1314-1318.
74. Kettenmann, H.; Hanisch, U.K.; Noda, M.; Verkhratsky, A. Physiology of microglia. Physiol. Rev., 2011, 91(2), 461-553.
75. Town, T.; Nikolic, V.; Tan, J. The microglial activation continuum: from innate to adaptive responses. J. Neuroinflammation, 2005, 2, 24.
76. Mantovani, A.; Sozzani, S.; Locati, M.; Allavena, P.; Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol., 2002, 23(11), 549-555.
77. Goerdt, S.; Orfanos, C.E. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity, 1999, 10(2), 137-142.
78. Koenigsknecht-Talboo, J.; Landreth, G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci., 2005, 25(36), 8240-8249.
79. Zelcer, N.; Khanlou, N.; Clare, R.; Jiang, Q.; Reed-Geaghan, E.G.; Landreth, G.E.; Vinters, H.V.; Tontonoz, P. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc. Natl. Acad. Sci. USA, 2007, 104(25), 10601-10606.
80. Colton, C.A.; Wilcock, D.M. Assessing activation states in microglia. CNS Neurol. Disord. Drug Targets, 2010, 9(2), 174-191.
81. Colton, C.A.; Mott, R.T.; Sharpe, H.; Xu, Q.; Van Nostrand, W.E.; Vitek, M.P. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation, 2006, 3, 27.
82. Jimenez, S.; Baglietto-Vargas, D.; Caballero, C.; Moreno-Gonzalez, I.; Torres, M.; Sanchez-Varo, R.; Ruano, D.; Vizuete, M.; Gutierrez, A.; Vitorica, J. Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J. Neurosci., 2008, 28(45), 11650-11661.
83. Flanary, B.E.; Streit, W.J. Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia, 2004, 45(1), 75-88.
84. Hickman, S.E.; Allison, E.K.; El Khoury, J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci., 2008, 28(33), 8354-8360.
85. Njie, E.G.; Boelen, E.; Stassen, F.R.; Steinbusch, H.W.; Borchelt, D.R.; Streit, W.J. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging, 2012, 33(1), e1-12.
86. Paresce, D.M.; Chung, H.; Maxfield, F.R.; Slow degradation of aggregates of the Alzheimer's disease amyloid beta-protein by microglial cells. J. Biol. Chem., 1997, 272(46), 29390-29397.
87. Frackowiak, J.; Wisniewski, H.M.; Wegiel, J.; Merz, G.S.; Iqbal, K.; Wang, K.C. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol., 1992, 84(3), 225-233.
88. Chung, H.; Brazil, M.I.; Soe, T.T.; Maxfield, F.R. Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer's amyloid beta-peptide by microglial cells. J. Biol. Chem., 1999, 274(45), 32301-32308.
89. Brazil, M.I.; Chung, H.; Maxfield, F.R. Effects of incorporation of immunoglobulin G and complement component C1q on uptake and degradation of Alzheimer's disease amyloid fibrils by microglia. J. Biol. Chem., 2000, 275(22), 16941-16947.
90. Heiple, J.M.; Wright, S.D.; Allen, N.S.; Silverstein, S.C. Macrophages form circular zones of very close apposition to IgGcoated surfaces. Cell Motil. Cytoskeleton, 1990, 15(4), 260-270.
91. Giulian, D.; Haverkamp, L.J.; Yu, J.H.; Karshin, W.; Tom, D.; Li, J.; Kirkpatrick, J.; Kuo, L.M.; Roher, A.E. Specific domains of beta-amyloid from Alzheimer plaque elicit neuron killing in human microglia. J. Neurosci., 1996, 16(19), 6021-6037.
92. London, J.A.; Biegel, D.; Pachter, J.S. Neurocytopathic effects of beta-amyloid-stimulated monocytes: a potential mechanism for central nervous system damage in Alzheimer disease. Proc. Natl. Acad. Sci. USA, 1996, 93(9), 4147-4152.
93. Griffin, W.S.; Stanley, L.C.; Ling, C.; White, L.; MacLeod, V.; Perrot, L.J.; White, C.L., 3rd., Araoz, C. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. USA, 1989, 86(19), 7611-7615.
94. Blum-Degen, D.; Muller, T.; Kuhn, W.; Gerlach, M.; Przuntek, H.; Riederer, P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci. Lett., 1995, 202(1-2), 17-20.
95. Akama, K.T.; Van Eldik, L.J. Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1betaand tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor-and NFkappaBinducing kinase-dependent signaling mechanism. J. Biol. Chem., 2000, 275(11), 7918-7924.
96. Mori, T.; Koyama, N.; Arendash, G.W.; Horikoshi-Sakuraba, Y.; Tan, J.; Town, T. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease. Glia, 2010, 58(3), 300-314.
97. Mrak, R.E.; Sheng, J.G.; Griffin, W.S. Glial cytokines in Alzheimer's disease: review and pathogenic implications. Hum. Pathol., 1995, 26(8), 816-823.
98. Tarkowski, E.; Andreasen, N.; Tarkowski, A.; Blennow, K. Intrathecal inflammation precedes development of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry, 2003, 74(9), 1200-1205.
99. Luccarini, I.; Grossi, C.; Traini, C.; Fiorentini, A.; Ed Dami, T.; Casamenti, F. Abeta plaque-associated glial reaction as a determinant of apoptotic neuronal death and cortical gliogenesis: a study in APP mutant mice. Neurosci. Lett., 2012, 506(1), 94-99.
100. Meda, L.; Cassatella, M.A.; Szendrei, G.I.; Otvos, L., Jr.; Baron, P.; Villalba, M.; Ferrari, D.; Rossi, F. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature, 1995, 374(6523), 647-650.
101. Sundaram, J.R.; Chan, E.S.; Poore, C.P.; Pareek, T.K.; Cheong, W.F.; Shui, G.; Tang, N.; Low, C.M.; Wenk, M.R.; Kesavapany, S. Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration. J. Neurosci., 2012, 32(3), 1020-1034.
102. Otth, C.; Concha, II, Arendt, T.; Stieler, J.; Schliebs, R.; Gonzalez-Billault, C.; Maccioni, R.B. AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J. Alzheimers Dis., 2002, 4(5), 417-430.
103. Town, T.; Zolton, J.; Shaffner, R.; Schnell, B.; Crescentini, R.; Wu, Y.; Zeng, J.; DelleDonne, A.; Obregon, D.; Tan, J.; Mullan, M. p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J. Neurosci. Res., 2002, 69(3), 362-372.
104. Cruz, J.C.; Tseng, H.C.; Goldman, J.A.; Shih, H.; Tsai, L.H. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron, 2003, 40(3), 471-483.
105. Noble, W.; Olm, V.; Takata, K.; Casey, E.; Mary, O.; Meyerson, J.; Gaynor, K.; LaFrancois, J.; Wang, L.; Kondo, T.; Davies, P.; Burns, M.; Veeranna, Nixon, R.; Dickson, D.; Matsuoka, Y.; Ahlijanian, M.; Lau, L.F.; Duff, K. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron, 2003, 38(4), 555-565.
106. Lopes, J.P.; Oliveira, C.R.; Agostinho, P. Role of cyclin-dependent kinase 5 in the neurodegenerative process triggered by amyloid-Beta and prion peptides: implications for Alzheimer's disease and prion-related encephalopathies. Cell Mol. Neurobiol., 2007, 27(7), 943-957.
107. Saito, T.; Konno, T.; Hosokawa, T.; Asada, A.; Ishiguro, K.; Hisanaga, S. p25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulumstressed neurons. J. Neurochem., 2007, 102(1), 133-140.
108. Velez-Pardo, C.; Ospina, G.G.; Jimenez del Rio, M. Abeta[25-35] peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism: involvement of H2O2, caspase-3, NF-kappaB, p53 and c-Jun. Neurotoxicology, 2002, 23(3), 351-365.
109. Tamagno, E.; Parola, M.; Guglielmotto, M.; Santoro, G.; Bardini, P.; Marra, L.; Tabaton, M.; Danni, O. Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosis. Free Radic. Biol. Med., 2003, 35(1), 45-58.
110. Tamagno, E.; Guglielmotto, M.; Bardini, P.; Santoro, G.; Davit, A.; Di Simone, D.; Danni, O.; Tabaton, M. Dehydroepiandrosterone reduces expression and activity of BACE in NT2 neurons exposed to oxidative stress. Neurobiol. Dis., 2003, 14(2), 291-301.
111. Chan, A.; Shea, T.B. Folate deprivation increases presenilin expression, gamma-secretase activity, and Abeta levels in murine brain: potentiation by ApoE deficiency and alleviation by dietary S-adenosyl methionine. J. Neurochem., 2007, 102(3), 753-760.
112. Agostinho, P.; Cunha, R.A.; Oliveira, C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease. Curr. Pharm. Des., 2010, 16(25), 2766-2778.
113. Ayasolla, K.; Khan, M.; Singh, A.K.; Singh, I. Inflammatory mediator and beta-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic. Biol. Med., 2004, 37(3), 325-338.
114. Rogers, J.T.; Bush, A.I.; Cho, H.H.; Smith, D.H.; Thomson, A.M.; Friedlich, A.L.; Lahiri, D.K.; Leedman, P.J.; Huang, X.; Cahill, C.M. Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease. Biochem. Soc. Trans., 2008, 36(Pt 6), 1282-1287.
115. Rogers, J.T.; Lahiri, D.K. Metal and inflammatory targets for Alzheimer's disease. Curr. Drug Targets, 2004, 5(6), 535-551.
116. Grathwohl, S.A.; Kalin, R.E.; Bolmont, 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.; Jucker, M. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci., 2009, 12(11), 1361-1363.
117. Herber, D.L.; Roth, L.M.; Wilson, D.; Wilson, N.; Mason, J.E.; Morgan, D.; Gordon, M.N. Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice. Exp. Neurol., 2004, 190(1), 245-253.
118. Wilcock, D.M.; Munireddy, S.K.; Rosenthal, A.; Ugen, K.E.; Gordon, M.N.; Morgan, D. Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol. Dis., 2004, 15(1), 11-20.
119. Wyss-Coray, T.; Lin, C.; Yan, F.; Yu, G.Q.; Rohde, M.; McConlogue, L.; Masliah, E.; Mucke, L. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat. Med., 2001, 7(5), 612-618.
120. Takata, K.; Kitamura, Y.; Yanagisawa, D.; Morikawa, S.; Morita, M.; Inubushi, T.; Tsuchiya, D.; Chishiro, S.; Saeki, M.; Taniguchi, T.; Shimohama, S.; Tooyama, I. Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett., 2007, 581(3), 475-478.
121. Simard, A.R.; Soulet, D.; Gowing, G.; Julien, J.P.; Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron, 2006, 49(4), 489-502.
122. 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.; Yednock, T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med., 2000, 6(8), 916-919.
123. Jantzen, P.T.; Connor, K.E.; DiCarlo, G.; Wenk, G.L.; Wallace, J.L.; Rojiani, A.M.; Coppola, D.; Morgan, D.; Gordon, M.N. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci., 2002, 22(6), 2246-2254.
124. Mandrekar, S.; Jiang, Q.; Lee, C.Y.; Koenigsknecht-Talboo, J.; Holtzman, D.M.; Landreth, G.E. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J. Neurosci., 2009, 29(13), 4252-4262.
125. Yuyama, K.; Sun, H.; Mitsutake, S.; Igarashi, Y. Sphingolipidmodulated Exosome Secretion Promotes Clearance of Amyloidbeta by Microglia. J. Biol. Chem., 2012, 287(14), 10977-10989.
126. Naert, G.; Rivest, S.; CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci., 2011, 31(16), 6208-6220.
127. Shaftel, S.S.; Kyrkanides, S.; Olschowka, J.A.; Miller, J.N.; Johnson, R.E.; O'Banion, M.K. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest., 2007, 117(6), 1595-1604.
128. Brandenburg, L.O.; Konrad, M.; Wruck, C.J.; Koch, T.; Lucius, R.; Pufe, T. Functional and physical interactions between formylpeptide-receptors and scavenger receptor MARCO and their involvement in amyloid beta 1-42-induced signal transduction in glial cells. J. Neurochem., 2010, 113(3), 749-760.
129. Tahara, K.; Kim, H.D.; Jin, J.J.; Maxwell, J.A.; Li, L.; Fukuchi, K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain, 2006, 129(Pt 11), 3006-3019.
130. Song, M.; Jin, J.; Lim, J.E.; Kou, J.; Pattanayak, A.; Rehman, J.A.; Kim, H.D.; Tahara, K.; Lalonde, R.; Fukuchi, K. TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease. J. Neuroinflammation, 2011, 8, 92.
131. DiCarlo, G.; Wilcock, D.; Henderson, D.; Gordon, M.; Morgan, D. Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol. Aging, 2001, 22(6), 1007-1012.
132. Doi, Y.; Mizuno, T.; Maki, Y.; Jin, S.; Mizoguchi, H.; Ikeyama, M.; Doi, M.; Michikawa, M.; Takeuchi, H.; Suzumura, A. Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Am. J. Pathol., 2009, 175(5), 2121-2132.
133. Sanchez-Ramos, J.; Song, S.; Sava, V.; Catlow, B.; Lin, X.; Mori, T.; Cao, C.; Arendash, G.W. Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience, 2009, 163(1), 55-72.
134. Boissonneault, V.; Filali, M.; Lessard, M.; Relton, J.; Wong, G.; Rivest, S. Powerful beneficial effects of macrophage colonystimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer's disease. Brain, 2009, 132(Pt 4), 1078-1092.
135. Boyd, T.D.; Bennett, S.P.; Mori, T.; Governatori, N.; Runfeldt, M.; Norden, M.; Padmanabhan, J.; Neame, P.; Wefes, I.; Sanchez-Ramos, J.; Arendash, G.W.; Potter, H.; GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J. Alzheimers Dis., 2010, 21(2), 507-518.
136. Lee, S.C.; Liu, W.; Brosnan, C.F.; Dickson, D.W. GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia, 1994, 12(4), 309-318.
137. Ridwan, S.; Bauer, H.; Frauenknecht, K.; von Pein, H.; Sommer, C.J. Distribution of granulocyte-monocyte colony-stimulating factor and its receptor alpha-subunit in the adult human brain with specific reference to Alzheimer's disease. J. Neural Transm., 2012.
138. Manczak, M.; Mao, P.; Nakamura, K.; Bebbington, C.; Park, B.; Reddy, P.H. Neutralization of granulocyte macrophage colonystimulating factor decreases amyloid beta 1-42 and suppresses microglial activity in a transgenic mouse model of Alzheimer's disease. Hum. Mol. Genet., 2009, 18(20), 3876-3893.
139. Hjorth, E.; Frenkel, D.; Weiner, H.; Schultzberg, M. Effects of immunomodulatory substances on phagocytosis of abeta(1-42) by human microglia. Int. J. Alzheimers Dis., 2010, 2010.
140. Kakimura, J.; Kitamura, Y.; Taniguchi, T.; Shimohama, S.; Gebicke-Haerter, P.J. Bip/GRP78-induced production of cytokines and uptake of amyloid-beta(1-42) peptide in microglia. Biochem. Biophys. Res. Commun., 2001, 281(1), 6-10.
141. Chakrabarty, P.; Jansen-West, K.; Beccard, A.; Ceballos-Diaz, C.; Levites, Y.; Verbeeck, C.; Zubair, A.C.; Dickson, D.; Golde, T.E.; Das, P. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J., 2010, 24(2), 548-559.
142. Wilcock, D.M.; Lewis, M.R.; Van Nostrand, W.E.; Davis, J.; Previti, M.L.; Gharkholonarehe, N.; Vitek, M.P.; Colton, C.A. Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J. Neurosci., 2008, 28(7), 1537-1545.
143. Wilcock, D.M.; Gharkholonarehe, N.; Van Nostrand, W.E.; Davis, J.; Vitek, M.P.; Colton, C.A. Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease. J. Neurosci., 2009, 29(25), 7957-7965.
144. Colton, C.A.; Wilcock, D.M.; Wink, D.A.; Davis, J.; Van Nostrand, W.E.; Vitek, M.P. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J. Alzheimers Dis., 2008, 15(4), 571-587.
145. Webster, S.; Lue, L.F.; Brachova, L.; Tenner, A.J.; McGeer, P.L.; Terai, K.; Walker, D.G.; Bradt, B.; Cooper, N.R.; Rogers, J. Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiol. Aging, 1997, 18(4), 415-421.
146. Wyss-Coray, T.; Yan, F.; Lin, A.H.; Lambris, J.D.; Alexander, J.J.; Quigg, R.J.; Masliah, E. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl. Acad. Sci. USA, 2002, 99(16), 10837-10842.
147. Maier, M.; Peng, Y.; Jiang, L.; Seabrook, T.J.; Carroll, M.C.; Lemere, C.A. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J. Neurosci., 2008, 28(25), 6333-6341.
148. Haga, S.; Ikeda, K.; Sato, M.; Ishii, T. Synthetic Alzheimer amyloid beta/A4 peptides enhance production of complement C3 component by cultured microglial cells. Brain Res., 1993, 601(1-2), 88-94.
149. Majumdar, A.; Capetillo-Zarate, E.; Cruz, D.; Gouras, G.K.; Maxfield, F.R. Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Mol. Biol. Cell, 2011, 22(10), 1664-1676.
150. Mawuenyega, K.G.; Sigurdson, W.; Ovod, V.; Munsell, L.; Kasten, T.; Morris, J.C.; Yarasheski, K.E.; Bateman, R.J. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science, 2010, 330(6012), 1774.
151. Schenk, D.; Barbour, R.; Dunn, W.; Gordon, G.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, M.; Liao, Z.; Lieberburg, I.; Motter, R.; Mutter, L.; Soriano, F.; Shopp, G.; Vasquez, N.; Vandevert, C.; Walker, S.; Wogulis, M.; Yednock, T; Games, D.; Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 1999, 400(6740), 173-177.
152. Morgan, D.; Diamond, D.M.; Gottschall, P.E.; Ugen, K.E.; Dickey, C.; Hardy, J.; Duff, K.; Jantzen, P.; DiCarlo, G.; Wilcock, D.; Connor, K.; Hatcher, J.; Hope, C.; Gordon, M.; Arendash, G.W. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature, 2000, 408(6815), 982-985.
153. Boche, D.; Denham, N.; Holmes, C.; Nicoll, J.A. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol., 2010, 120(3), 369-384.
154. Check, E. Nerve inflammation halts trial for Alzheimer's drug. Nature, 2002, 415(6871), 462.
155. Town, T.; Vendrame, M.; Patel, A.; Poetter, D.; DelleDonne, A.; Mori, T.; Smeed, R.; Crawford, F.; Klein, T.; Tan, J.; Mullan, M. Reduced Th1 and enhanced Th2 immunity after immunization with Alzheimer's beta-amyloid(1-42). J. Neuroimmunol., 2002, 132(1-2), 49-59.
156. Lemere, C.A.; Maron, R.; Selkoe, D.J.; Weiner, H.L. Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer's disease. DNA Cell Biol., 2001, 20(11), 705-711.
157. Lemere, C.A.; Maron, R.; Spooner, E.T.; Grenfell, T.J.; Mori, C.; Desai, R.; Hancock, W.W.; Weiner, H.L.; Selkoe, D.J. Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Ann. NY Acad. Sci., 2000, 920, 328-331.
158. Nikolic, W.V.; Bai, Y.; Obregon, D.; Hou, H.; Mori, T.; Zeng, J.; Ehrhart, J.; Shytle, R.D.; Giunta, B.; Morgan, D.; Town, T.; Tan, J. Transcutaneous beta-amyloid immunization reduces cerebral betaamyloid deposits without T cell infiltration and microhemorrhage. Proc. Natl. Acad. Sci. USA, 2007, 104(7), 2507-2512.
159. Das, P.; Murphy, M.P.; Younkin, L.H.; Younkin, S.G.; Golde, T.E. Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol. Aging, 2001, 22(5), 721-727.
160. Corder, E.H.; Robertson, K.; Lannfelt, L.; Bogdanovic, N.; Eggertsen, G.; Wilkins, J.; Hall, C. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat. Med., 1998, 4(10), 1182-1184.
161. Hollingworth, P.; Harold, D.; Sims, R.; Gerrish, A.; Lambert, J.C.; Carrasquillo, M.M.; Abraham, R.; Hamshere, M.L.; Pahwa, J.S.; Moskvina, V.; Dowzell, K.; Jones, N.; Stretton, A.; Thomas, C.; Richards, A.; Ivanov, D.; Widdowson, C.; Chapman, J.; Lovestone, S.; Powell, J.; Proitsi, P.; Lupton, M.K.; Brayne, C.; Rubinsztein, D.C.; Gill, M.; Lawlor, B.; Lynch, A.; Brown, K.S.; Passmore, P.A.; Craig, D.; McGuinness, B.; Todd, S.; Holmes, C.; Mann, D.; Smith, A.D.; Beaumont, H.; Warden, D.; Wilcock, G.; Love, S.; Kehoe, P.G.; Hooper, N.M.; Vardy, E.R.; Hardy, J.; Mead, S.; Fox, N.C.; Rossor, M.; Collinge, J.; Maier, W.; Jessen, F.; Ruther, E.; Schurmann, B.; Heun, R.; Kolsch, H.; van den Bussche, H.; Heuser, I.; Kornhuber, J.; Wiltfang, J.; Dichgans, M.; Frolich, L.; Hampel, H.; Gallacher, J.; Hull, M.; Rujescu, D.; Giegling, I.; Goate, A.M.; Kauwe, J.S.; Cruchaga, C.; Nowotny, P.; Morris, J.C.; Mayo, K.; Sleegers, K.; Bettens, K.; Engelborghs, S.; De Deyn, P.P.; Van Broeckhoven, C.; Livingston, G.; Bass, N.J.; Gurling, H.; McQuillin, A.; Gwilliam, R.; Deloukas, P.; Al-Chalabi, A.; Shaw, C.E.; Tsolaki, M.; Singleton, A.B.; Guerreiro, R.; Muhleisen, T.W.; Nothen, M.M.; Moebus, S.; Jockel, K.H.; Klopp, N.; Wichmann, H.E.; Pankratz, V.S.; Sando, S.B.; Aasly, J.O.; Barcikowska, M.; Wszolek, Z.K.; Dickson, D.W.; Graff-Radford, N.R.; Petersen, R.C.; van Duijn, C.M.; Breteler, M.M.; Ikram, M.A.; DeStefano, A.L.; Fitzpatrick, A.L.; Lopez, O.; Launer, L.J.; Seshadri, S.; Berr, C.; Campion, D.; Epelbaum, J.; Dartigues, J.F.; Tzourio, C.; Alperovitch, A.; Lathrop, M.; Feulner, T.M.; Friedrich, P.; Riehle, C.; Krawczak, M.; Schreiber, S.; Mayhaus, M.; Nicolhaus, S.; Wagenpfeil, S.; Steinberg, S.; Stefansson, H.; Stefansson, K.; Snaedal, J.; Bjornsson, S.; Jonsson, P.V.; Chouraki, V.; Genier-Boley, B.; Hiltunen, M.; Soininen, H.; Combarros, O.; Zelenika, D.; Delepine, M.; Bullido, M.J.; Pasquier, F.; Mateo, I.; Frank-Garcia, A.; Porcellini, E.; Hanon, O.; Coto, E.; Alvarez, V.; Bosco, P.; Siciliano, G.; Mancuso, M.; Panza, F.; Solfrizzi, V.; Nacmias, B.; Sorbi, S.; Bossu, P.; Piccardi, P.; Arosio, B.; Annoni, G.; Seripa, D.; Pilotto, A.; Scarpini, E.; Galimberti, D.; Brice, A.; Hannequin, D.; Licastro, F.; Jones, L.; Holmans, P.A.; Jonsson, T.; Riemenschneider, M.; Morgan, K.; Younkin, S.G.; Owen, M.J.; O'Donovan, M.; Amouyel, P.; Williams, J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet., 2011, 43(5), 429-435.
162. Naj, A.C.; Jun, G.; Beecham, G.W.; Wang, L.S.; Vardarajan, B.N.; Buros, J.; Gallins, P.J.; Buxbaum, J.D.; Jarvik, G.P.; Crane, P.K.; Larson, E.B.; Bird, T.D.; Boeve, B.F.; Graff-Radford, N.R.; De Jager, P.L.; Evans, D.; Schneider, J.A.; Carrasquillo, M.M.; Ertekin-Taner, N.; Younkin, S.G.; Cruchaga, C.; Kauwe, J.S.; Nowotny, P.; Kramer, P.; Hardy, J.; Huentelman, M.J.; Myers, A.J.; Barmada, M.M.; Demirci, F.Y.; Baldwin, C.T.; Green, R.C.; Rogaeva, E.; St George-Hyslop, P.; Arnold, S.E.; Barber, R.; Beach, T.; Bigio, E.H.; Bowen, J.D.; Boxer, A.; Burke, J.R.; Cairns, N.J.; Carlson, C.S.; Carney, R.M.; Carroll, S.L.; Chui, H.C.; Clark, D.G.; Corneveaux, J.; Cotman, C.W.; Cummings, J.L.; DeCarli, C.; DeKosky, S.T.; Diaz-Arrastia, R.; Dick, M.; Dickson, D.W.; Ellis, W.G.; Faber, K.M.; Fallon, K.B.; Farlow, M.R.; Ferris, S.; Frosch, M.P.; Galasko, D.R.; Ganguli, M.; Gearing, M.; Geschwind, D.H.; Ghetti, B.; Gilbert, J.R.; Gilman, S.; Giordani, B.; Glass, J.D.; Growdon, J.H.; Hamilton, R.L.; Harrell, L.E.; Head, E.; Honig, L.S.; Hulette, C.M.; Hyman, B.T.; Jicha, G.A.; Jin, L.W.; Johnson, N.; Karlawish, J.; Karydas, A.; Kaye, J.A.; Kim, R.; Koo, E.H.; Kowall, N.W.; Lah, J.J.; Levey, A.I.; Lieberman, A.P.; Lopez, O.L.; Mack, W.J.; Marson, D.C.; Martiniuk, F.; Mash, D.C.; Masliah, E.; McCormick, W.C.; McCurry, S.M.; McDavid, A.N.; McKee, A.C.; Mesulam, M.; Miller, B.L.; Miller, C.A.; Miller, J.W.; Parisi, J.E.; Perl, D.P.; Peskind, E.; Petersen, R.C.; Poon, W.W.; Quinn, J.F.; Rajbhandary, R.A.; Raskind, M.; Reisberg, B.; Ringman, J.M.; Roberson, E.D.; Rosenberg, R.N.; Sano, M.; Schneider, L.S.; Seeley, W.; Shelanski, M.L.; Slifer, M.A.; Smith, C.D.; Sonnen, J.A.; Spina, S.; Stern, R.A.; Tanzi, R.E.; Trojanowski, J.Q.; Troncoso, J.C.; Van Deerlin, V.M.; Vinters, H.V.; Vonsattel, J.P.; Weintraub, S.; Welsh-Bohmer, K.A.; Williamson, J.; Woltjer, R.L.; Cantwell, L.B.; Dombroski, B.A.; Beekly, D.; Lunetta, K.L.; Martin, E.R.; Kamboh, M.I.; Saykin, A.J.; Reiman, E.M.; Bennett, D.A.; Morris, J.C.; Montine, T.J.; Goate, A.M.; Blacker, D.; Tsuang, D.W.; Hakonarson, H.; Kukull, W.A.; Foroud, T.M.; Haines, J.L.; Mayeux, R.; Pericak-Vance, M.A.; Farrer, L.A.; Schellenberg, G.D. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet., 2011, 43(5), 436-441.
163. Cudaback, E.; Li, X.; Montine, K.S.; Montine, T.J.; Keene, C.D. Apolipoprotein E isoform-dependent microglia migration. FASEB J., 2011, 25(6), 2082-2091.
164. Brown, C.M.; Wright, E.; Colton, C.A.; Sullivan, P.M.; Laskowitz, D.T.; Vitek, M.P. Apolipoprotein E isoform mediated regulation of nitric oxide release. Free Radic. Biol. Med., 2002, 32(11), 1071-1075.
165. Colton, C.A.; Brown, C.M.; Vitek, M.P. Sex steroids, APOE genotype and the innate immune system. Neurobiol. Aging, 2005, 26(3), 363-372.
166. Vitek, M.P.; Brown, C.M.; Colton, C.A. APOE genotype-specific differences in the innate immune response. Neurobiol. Aging, 2009, 30(9), 1350-1360.
167. Czapiga, M.; Colton, C.A. Microglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport. J. Neuroimmunol., 2003, 134(1-2), 44-51.
168. Maezawa, I.; Maeda, N.; Montine, T.J.; Montine, K.S. Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice. J. Neuroinflammation, 2006, 3, 10.
169. Maezawa, I.; Nivison, M.; Montine, K.S.; Maeda, N.; Montine, T.J. Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J., 2006, 20(6), 797-799.
170. Ophir, G.; Amariglio, N.; Jacob-Hirsch, J.; Elkon, R.; Rechavi, G.; Michaelson, D.M. Apolipoprotein E4 enhances brain inflammation by modulation of the NF-kappaB signaling cascade. Neurobiol. Dis., 2005, 20(3), 709-718.
171. Lee, C.Y.; Tse, W.; Smith, J.D.; Landreth, G.E. Apolipoprotein E promotes beta-amyloid trafficking and degradation by modulating microglial cholesterol levels. J. Biol. Chem., 2012, 287(3), 2032-2044.
172. Jiang, Q.; Lee, C.Y.; Mandrekar, S.; Wilkinson, B.; Cramer, P.; Zelcer, N.; Mann, K.; Lamb, B.; Willson, T.M.; Collins, J.L.; Richardson, J.C.; Smith, J.D.; Comery, T.A.; Riddell, D.; Holtzman, D.M.; Tontonoz, P.; Landreth, G.E. ApoE promotes the proteolytic degradation of Abeta. Neuron, 2008, 58(5), 681-693.
173. Castellano, J.M.; Kim, J.; Stewart, F.R.; Jiang, H.; DeMattos, R.B.; Patterson, B.W.; Fagan, A.M.; Morris, J.C.; Mawuenyega, K.G.; Cruchaga, C.; Goate, A.M.; Bales, K.R.; Paul, S.M.; Bateman, R.J.; Holtzman, D.M. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci. Transl. Med., 2011, 3(89), 89ra57.
174. Bales, K.R.; Liu, F.; Wu, S.; Lin, S.; Koger, D.; DeLong, C.; Hansen, J.C.; Sullivan, P.M.; Paul, S.M. Human APOE isoformdependent effects on brain beta-amyloid levels in PDAPP transgenic mice. J. Neurosci., 2009, 29(21), 6771-6779.
175. Hirsch-Reinshagen, V.; Maia, L.F.; Burgess, B.L.; Blain, J.F.; Naus, K.E.; McIsaac, S.A.; Parkinson, P.F.; Chan, J.Y.; Tansley, G.H.; Hayden, M.R.; Poirier, J.; Van Nostrand, W.; Wellington, C.L. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J. Biol. Chem., 2005, 280(52), 43243-43256.
176. Wahrle, S.E.; Jiang, H.; Parsadanian, M.; Hartman, R.E.; Bales, K.R.; Paul, S.M.; Holtzman, D.M. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J. Biol. Chem., 2005, 280(52), 43236-43242.
177. Mandrekar-Colucci, S.; Karlo, J.C.; Landreth, G.E. Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptorgamma-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease. J. Neurosci., 2012, 32(30), 10117-10128.
178. Shie, F.S.; Nivison, M.; Hsu, P.C.; Montine, T.J. Modulation of microglial innate immunity in Alzheimer's disease by activation of peroxisome proliferator-activated receptor gamma. Curr. Med. Chem., 2009, 16(6), 643-651.
179. Cramer, P.E.; Cirrito, J.R.; Wesson, D.W.; Lee, C.Y.; Karlo, J.C.; Zinn, A.E.; Casali, B.T.; Restivo, J.L.; Goebel, W.D.; James, M.J.; Brunden, K.R.; Wilson, D.A.; Landreth, G.E. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science, 2012, 335(6075), 1503-1506.
180. Deane, R.; Singh, I.; Sagare, A.P.; Bell, R.D.; Ross, N.T.; LaRue, B.; Love, R.; Perry, S.; Paquette, N.; Deane, R.J.; Thiyagarajan, M.; Zarcone, T.; Fritz, G.; Friedman, A.E.; Miller, B.L.; Zlokovic, B.V. A multimodal RAGE-specific inhibitor reduces amyloid betamediated brain disorder in a mouse model of Alzheimer disease. J. Clin. Invest., 2012, 122(4), 1377-1392.
181. Liu, S.; Liu, Y.; Hao, W.; Wolf, L.; Kiliaan, A.J.; Penke, B.; Rube, C.E.; Walter, J.; Heneka, M.T.; Hartmann, T.; Menger, M.D.; Fassbender, K. TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. J. Immunol., 2012, 188(3), 1098-1107.
182. Wilkinson, K.; Boyd, J.D.; Glicksman, M.; Moore, K.J.; El Khoury, J. A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J. Biol. Chem., 2011, 286(40), 34914-34922.
183. Li, M.O.; Wan, Y.Y.; Sanjabi, S.; Robertson, A.K.; Flavell, R.A. Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol., 2006, 24, 99-146.
184. Wyss-Coray, T.; Lin, C.; Sanan, D.A.; Mucke, L.; Masliah, E. Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am. J. Pathol., 2000, 156(1), 139-150.
185. Wyss-Coray, T.; Masliah, E.; Mallory, M.; McConlogue, L.; Johnson-Wood, K.; Lin, C.; Mucke, L. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature, 1997, 389(6651), 603-606.
186. Brionne, T.C.; Tesseur, I.; Masliah, E.; Wyss-Coray, T. Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron, 2003, 40(6), 1133-1145.
187. Magnus, T.; Chan, A.; Linker, R.A.; Toyka, K.V.; Gold, R. Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system. J. Neuropathol. Exp. Neurol., 2002, 61(9), 760-766.
188. Frautschy, S.A.; Cole, G.M.; Baird, A. Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer betaamyloid. Am. J. Pathol., 1992, 140(6), 1389-1399.
189. Tesseur, I.; Zou, K.; Esposito, L.; Bard, F.; Berber, E.; Can, J.V.; Lin, A.H.; Crews, L.; Tremblay, P.; Mathews, P.; Mucke, L.; Masliah, E.; Wyss-Coray, T. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J. Clin. Invest., 2006, 116(11), 3060-3069.
190. Tichauer, J.E.; von Bernhardi, R. Transforming growth factor-beta stimulates beta amyloid uptake by microglia through Smad3-dependent mechanisms. J. Neurosci. Res., 2012.
191. Salins, P.; He, Y.; Olson, K.; Glazner, G.; Kashour, T.; Amara, F. TGF-beta1 is increased in a transgenic mouse model of familial Alzheimer's disease and causes neuronal apoptosis. Neurosci. Lett., 2008, 430(1), 81-86.
192. Laouar, Y.; Sutterwala, F.S.; Gorelik, L.; Flavell, R.A. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferongamma. Nat. Immunol., 2005, 6(6), 600-607.
193. Laouar, Y.; Town, T.; Jeng, D.; Tran, E.; Wan, Y.; Kuchroo, V.K.; Flavell, R.A. TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA, 2008, 105(31), 10865-10870.
194. Town, T.; Laouar, Y.; Pittenger, C.; Mori, T.; Szekely, C.A.; Tan, J.; Duman, R.S.; Flavell, R.A. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat. Med., 2008, 14(6), 681-687.
195. Gate, D.; Rezai-Zadeh, K.; Jodry, D.; Rentsendorj, A.; Town, T. Macrophages in Alzheimer's disease: the blood-borne identity. J. Neural Transm., 2010, 117(8), 961-970.
196. Rezai-Zadeh, K.; Gate, D.; Town, T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J. Neuroimmune Pharmacol., 2009, 4(4), 462-475.
197. Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.C.; Gelpi, E.; Halle, A.; Korte, M.; Latz, E.; Golenbock DT. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 2013, 493(7434), 674-678.