Microglial activation in Alzheimer's disease

Current Alzheimer Research

Volumn 6, Issue 6, 2009, Pages 554-563

  Schlachetzki, Johannes C M ^a   Hüll, Michael ^a  

^a UNIVERSITY OF FREIBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; ATORVASTATIN; CANNABINOID; CD11B ANTIGEN; CD14 ANTIGEN; CD18 ANTIGEN; CELECOXIB; CELL RECEPTOR; COMPLEMENT COMPONENT C3 RECEPTOR; CURCUMIN; DEXAMETHASONE; IBUPROFEN; INDOMETACIN; INTERLEUKIN 10; INTERLEUKIN 4; MINOCYCLINE; MONOCYTE CHEMOTACTIC PROTEIN 1; NAPROXEN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROSTAGLANDIN E RECEPTOR; PROSTAGLANDIN E3 RECEPTOR; PROSTAGLANDIN E4 RECEPTOR; RESVERATROL; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 9; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ACTIVE IMMUNIZATION; ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; BLOOD BRAIN BARRIER; BONE MARROW CELL; BRAIN METABOLISM; CELL ACTIVATION; CELL FUNCTION; CHRONIC INFLAMMATION; COGNITION; COMPLEMENT ACTIVATION; DISEASE MODEL; DRUG EFFECT; DRUG EFFICACY; DRUG PENETRATION; GENE EXPRESSION; HUMAN; IMMUNOTHERAPY; MACROPHAGE; MICROGLIA; MONOCYTE; NEUROFIBRILLARY TANGLE; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; PASSIVE IMMUNIZATION; PERIPHERAL BLOOD MONONUCLEAR CELL; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN DEGRADATION; PROTEIN EXPRESSION; RECEPTOR BINDING; REVIEW; TREATMENT OUTCOME; ANIMAL; BRAIN; INFLAMMATION; METABOLISM; MOUSE; PATHOLOGY;

ALZHEIMER DISEASE; AMYLOID BETA-PROTEIN; ANIMALS; BRAIN; INFLAMMATION; MICE; MICROGLIA;

EID: 73949103253     PISSN: 15672050     EISSN: None     Source Type: Journal    
DOI: 10.2174/156720509790147179     Document Type: Review

References (115)

1. Nimmerjahn A, Kirchhoff F, Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314-8 (2005).
2. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8: 752-8 (2005).
3. Rogers J, Lue LF. Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease. Neurochem Int 39: 333-40 (2001).
4. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14: 837-42 (2008).
5. D'Amore JD, Kajdasz ST, McLellan ME, Bacskai BJ, Stern EA, Hyman, BT. In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories. J Neuropathol Exp Neurol 62: 137-45 (2003).
6. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai, BJ. Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59: 214-25 (2008).
7. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383-421 (2000).
8. Park KM, Yule DI, Bowers WJ. Tumor necrosis factor-alpha potentiates intraneuronal Ca2+ signaling via regulation of the inositol 1,4,5-trisphosphate receptor. J Biol Chem 283: 33069-79 (2008).
9. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53: 337-51 (2007).
10. Wirths O, Breyhan H, Marcello A, Cotel MC, Bruck W, Bayer, TA. Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging (2008) [Epub ahead of print].
11. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation. 2: 22 (2005).
12. Rogers J, Strohmeyer R, Kovelowski CJ, Li R. Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40: 260-9 (2002).
13. Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, et al. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J Clin Invest 116: 3060-9 (2006).
14. Wyss-Coray T. Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's. Curr Alzheimer Res 3: 191-5 (2006).
15. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129: 3006-19 (2006).
16. Ebert S, Gerber J, Bader S, Muhlhauser F, Brechtel K, Mitchell TJ, et al. Dose-dependent activation of microglial cells by Toll-like receptor agonists alone and in combination. J Neuroimmunol 159: 87-96 (2005).
17. Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem 20: 947-56 (2007).
18. Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, et al. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem 281: 3651-9 (2006).
19. Richard KL, 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 28: 5784-93 (2008).
20. Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain 128: 1778-89 (2005).
21. Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, et al. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J 18: 203-5 (2004).
22. Andreasson KI, Savonenko A, Vidensky S, Goellner JJ, Zhang Y, Shaffer A, et al. Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci 21: 8198-209 (2001).
23. Slawik H, Volk B, Fiebich B, Hull M. Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum. Neurochem Int 45: 653-60 (2004).
24. Hoshino T, Nakaya T, Homan T, Tanaka K, Sugimoto Y, Araki W, et al. Involvement of prostaglandin E2 in production of amyloidbeta peptides both in vitro and in vivo. J Biol Chem 282: 32676-88 (2007).
25. Shie FS, Breyer RM, Montine TJ. Microglia lacking E Prostanoid Receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity. Am J Pathol 166: 1163-72 (2005).
26. Liang X, Wang Q, Hand T, Wu L, Breyer RM, Montine TJ, et al. Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease. J Neurosci 25: 10180-7 (2005).
27. Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci USA 99: 10837-42 (2002).
28. Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. 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 28: 6333-41 (2008).
29. Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 84: 225-33 (1992).
30. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9: 857-65 (2008).
31. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. ApoE promotes the proteolytic degradation of Abeta. Neuron 58: 681-93 (2008).
32. Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26: 4985-94 (2006).
33. Mayeux R. Apolipoprotein E, Alzheimer disease, and African Americans. Arch Neurol 60: 161-3 (2003).
34. Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, et al. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci USA 104: 10601-6 (2007).
35. Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O'Banion, MK. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 117: 1595-604 (2007).
36. Morgan D, Gordon MN, Tan J, Wilcock D, Rojiani AM. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. J Neuropathol Exp Neurol 64: 743-53 (2005).
37. Yamamoto M, Horiba M, Buescher JL, Huang D, Gendelman HE, Ransohoff RM, et al. Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. Am J Pathol 166: 1475-85 (2005).
38. Eikelenboom P, Veerhuis R, Familian A, Hoozemans JJ, van Gool WA, Rozemuller AJ. Neuroinflammation in plaque and vascular beta-amyloid disorders: clinical and therapeutic implications. Neurodegener Dis 5: 190-3 (2008).
39. Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451: 720-4 (2008).
40. Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28: 4283-92 (2008).
41. Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, et al. Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett 581: 475-8 (2007).
42. Schroeter M, Jander S, Huitinga I, Witte OW, Stoll G. Phagocytic response in photochemically induced infarction of rat cerebral cortex. The role of resident microglia. Stroke 28: 382-6 (1997).
43. Streit WJ, Miller KR, Lopes KO, Njie E. Microglial degeneration in the aging brain--bad news for neurons? Front Biosci 13: 3423-38 (2008).
44. Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 18: 315-21 (2005).
45. Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 25: 8240-9 (2005).
46. Lyons A, Griffin RJ, Costelloe CE, Clarke RM, Lynch MA. IL-4 attenuates the neuroinflammation induced by amyloid-beta in vivo and in vitro. J Neurochem 101: 771-81 (2007).
47. Zhao W, Xie W, Xiao Q, Beers DR, Appel SH. Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 99: 1176-87 (2006).
48. Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3: 27 (2006).
49. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, et al. 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 28: 11650-61 (2008).
50. Floden AM, Combs CK. Beta-amyloid stimulates murine postnatal and adult microglia cultures in a unique manner. J Neurosci 26: 4644-8 (2006).
51. Hoozemans JJ, Veerhuis R, Janssen I, van Elk EJ, Rozemuller AJ, Eikelenboom P. The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease. Brain Res 951: 218-26 (2002).
52. Xie Z, Morgan TE, Rozovsky I, Finch CE. Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp Neurol 182: 135-41 (2003).
53. Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, et al. Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2: e355 (2005).
54. Das P, Murphy MP, Younkin LH, Younkin SG, Golde TE. Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol Aging 22: 721-7 (2001).
55. Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 28: 8354-60 (2008).
56. Alliot F, Godin I, Pessac B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117: 145-52 (1999).
57. Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7: 1356-61 (2001).
58. Simard AR, Rivest S. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 18: 998-1000 (2004).
59. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10: 1538-43 (2007).
60. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10: 1544-53 (2007).
61. Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 21: 1619-27 (2001).
62. Malm TM, Koistinaho M, Parepalo M, Vatanen T, Ooka A, Karlsson S, et al. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 18: 134-42 (2005).
63. Stalder AK, Ermini F, Bondolfi L, Krenger W, Burbach GJ, Deller T, et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci 25: 11125-32 (2005).
64. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49: 489-502 (2006).
65. 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 51: 135-8 (1997).
66. El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13: 432-8 (2007).
67. Britschgi M, Wyss-Coray, T. Immune cells may fend off Alzheimer disease. Nat Med 13: 408-9 (2007).
68. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, et al. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14: 681-7 (2008).
69. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24: 99-146 (2006).
70. Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, et al. Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell 18: 1490-6 (2007).
71. Frenkel D, Maron R, Burt DS, Weiner HL. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears betaamyloid in a mouse model of Alzheimer disease. J Clin Invest 115: 2423-33 (2005).
72. Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, et al. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci USA 103: 11784-9 (2006).
73. Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur J Neurosci 26: 413-6 (2007).
74. Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 20: 5709-14 (2000).
75. Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, et al. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal antiinflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci 22: 2246-54 (2002).
76. Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, et al. Cognitive function over time in the Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol 65: 896-905 (2008).
77. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53: 776-82 (2006).
78. Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, et al. Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci 27: 3057-63 (2007).
79. Malm TM, Magga J, Kuh GF, Vatanen T, Koistinaho M, Koistinaho J. Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease. Glia 56: 1767-79 (2008).
80. Familian A, Eikelenboom P, Veerhuis R. Minocycline does not affect amyloid beta phagocytosis by human microglial cells. Neurosci Lett 416: 87-91 (2007).
81. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-diseaselike pathology in the PDAPP mouse. Nature 400: 173-7 (1999).
82. Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, et al. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 7: 369-72 (2001).
83. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9: 448-52 (2003).
84. Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, et al. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 65: 1040-8 (2006).
85. Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ. A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28: 286-92 (2007).
86. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid betapeptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6: 916-9 (2000).
87. Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci 22: 7873-8 (2002).
88. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci 23: 8532-8 (2003).
89. Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, Ugen KE, et al. Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 23: 3745-51 (2003).
90. Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D. Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15: 11-20 (2004).
91. Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol 14: 11-20 (2004).
92. Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29: 4252-62 (2009).
93. Brody DL, Holtzman DM. Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci 31: 175-93 (2008).
94. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372: 216-23 (2008).
95. Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, et al. Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease. Am J Pathol 165: 2197-206 (2004).
96. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128: 1442-53 (2005).
97. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci 20: 558-67 (2000).
98. Strohmeyer R, Kovelowski CJ, Mastroeni D, Leonard B, Grover A, Rogers J. Microglial responses to amyloid beta peptide opsonization and indomethacin treatment. J Neuroinflammation 2: 18 (2005).
99. Shie FS, Montine KS, Breyer RM, Montine TJ. Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity. Glia 52: 70-7 (2005).
100. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70: 1672-7 (2008).
101. de Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, et al. No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial. PLoS ONE 3: e1475 (2008).
102. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA 93: 14014-9 (1996).
103. Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID. Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem 282: 15208-16 (2007).
104. Cordle A, Landreth G. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. J Neurosci 25: 299-307 (2005).
105. Bi X, Baudry M, Liu J, Yao Y, Fu L, Brucher F, et al. Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia. J Biol Chem 279: 48238-45 (2004).
106. Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G. Mechanisms of statin-mediated inhibition of small Gprotein function. J Biol Chem 280: 34202-9 (2005).
107. Sparks DL, Connor DJ, Sabbagh MN, Petersen RB, Lopez J, Browne P. Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial. Acta Neurol Scand Suppl 185: 3-7 (2006).
108. Esposito G, Scuderi C, Savani C, Steardo L, Jr., De Filippis D, Cottone P, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol 151: 1272-9 (2007).
109. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25: 1904-13 (2005).
110. Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, et al. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49: 67-79 (2006).
111. Kang G, Kong PJ, Yuh YJ, Lim SY, Yim SV, Chun W, et al. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells. J Pharmacol Sci 94: 325-8 (2004).
112. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21: 8370-7 (2001).
113. Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, et al. Innate immunity and transcription of MGATIII and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci USA 104: 12849-54 (2007).
114. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, et al. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 280: 40364-74 (2005).
115. Candelario-Jalil E, de Oliveira AC, Graf S, Bhatia HS, Hull M, Munoz E, et al. Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia. J Neuroinflammation 4: 25 (2007).