Microglia in alzheimer’s disease: The good, the bad and the ugly

Current Alzheimer Research

Volumn 13, Issue 4, 2016, Pages 370-380

  Tejera, Dario ^a   Heneka, Michael T ^a,b  

^a UNIVERSITY OF BONN   (Germany)

^b GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

Author keywords

Alzheimer s; Amyloid ; Cytokines; Microglia; Neurodegeneration; Neuroinflammation

Indexed keywords

AMYLOID BETA PROTEIN; CHEMOKINE; CYTOKINE; TAU PROTEIN;

ALZHEIMER DISEASE; ARTICLE; BRAIN FUNCTION; CELL ACTIVATION; COMORBIDITY; COMPLEMENT SYSTEM; DEMENTIA; HISTOLOGY; HUMAN; INNATE IMMUNITY; MICROGLIA; MOLECULAR IMAGING; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; ANIMAL; BRAIN; PATHOLOGY; PHYSIOLOGY;

ALZHEIMER DISEASE; ANIMALS; BRAIN; HUMANS; MICROGLIA;

EID: 84964037904     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205013666151116125012     Document Type: Article

References (135)

1. Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7): 463-77 (2014).
2. Gyoneva S, Davalos D, Biswas D, Swanger SA, Garnier-Amblard E, Loth F, et al. Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia 62: 1345-60 (2014).
3. Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8(4): e60921 (2013).
4. Block ML, Zecca L, Hong J. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8: 57-69 (2007).
5. Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer’s disease. Aging Cell 13(4): 1-12 (2014).
6. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005): 841-5 (2010).
7. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16(3): 273-80 (2013).
8. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1): 151-70 (1990).
9. 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(6): 752-8 (2005).
10. Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11): 1387-94 (2007).
11. Harry GJ. Microglia during development and aging. Pharmacol Ther 139: 313-26 (2013).
12. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron 77(1): 10-18 (2013).
13. Tremblay M-E, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8(11): e1000527 (2010).
14. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic Pruning by Microglia Is Necessary for Normal Brain Development. Science 333: 1456-8 (2011).
15. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4): 691-705 (2012).
16. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, Lafaille JJ, et al. Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor. Cell 155(7): 1596-609 (2013).
17. Erion JR, Wosiski-Kuhn M, Dey A, Hao S, Davis CL, Pollock NK, et al. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci 34(7): 2618-31 (2014).
18. d’Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, et al. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflamm 9(1): 31 (2012).
19. Lucin KM, O’Brien CE, Bieri G, Czirr E, Mosher KI, Abbey RJ, et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 79(5): 873-86 (2013).
20. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5): 300-12 (2014).
21. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8): 312-8 (1995).
22. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 13: 453-61 (2008).
23. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159(6): 1312-26 (2014).
24. Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159(6): 1327-40 (2014).
25. Farber K, Pannasch U, Kettenmann H. Dopamine and noradrenaline control distinct functions in rodent microglial cells. Mol Cell Neurosci 29(1): 128-38 (2005).
26. Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Thiele A, Heneka MT. Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice. Neuroscience 176: 396-407 (2011).
27. Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107(13): 6058-63 (2010).
28. Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27: 119-45 (2009).
29. Streit WJ. Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 77(1): 1-8 (2004).
30. Mackenzie IR. Anti-inflammatory drugs and Alzheimer-type pathology in aging. Neurology 54(3): 732-4 (2000).
31. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414(6860): 212-6 (2001).
32. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9(7): 907-13 (2003).
33. Yan SD, Roher A, Chaney M, Zlokovic B, Schmidt AM, Stern D. Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide. Biochim Biophys Acta 1502(1): 145-57 (2000).
34. Matrone C, Djelloul M, Taglialatela G, Perrone L. Review Inflammatory risk factors and pathologies promoting Alzheimer’s disease progression: is RAGE the key? Histol Histopathol 29: 1-15 (2014).
35. Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, et al. RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 23(20): 4096-105 (2004).
36. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5): 429-35 (2011).
37. Lajaunias F, Dayer J-M, Chizzolini C. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur J Immunol 35(1): 243-51 (2005).
38. Griciuc A, Serrano-pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78: 631-43 (2013).
39. Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16(7): 848-50 (2013).
40. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2): 117-27 (2013).
41. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson P V, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2): 107-16 (2013).
42. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang L-C, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12): 1896-905 (2013).
43. Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 177(4): 2051-5 (2006).
44. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, et al. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177(6): 3520-4 (2006).
45. Takahashi K, Rochford CDP, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4): 647-57 (2005).
46. Heneka MT, O’Banion MK. Inflammatory processes in Alzheimer’s disease. J Neuroimmunol 184(1-2): 69-91 (2007).
47. Frank S, Burbach GJ, Bonin M, Walter M, Streit W, Bechmann I, et al. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56(13): 1438-47 (2008).
48. Hickman SE, El Khoury J. TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem Pharmacol 88(4): 495-8 (2014).
49. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160: 1061-71 (2015)
50. Krauthausen M, Kummer MP, Zimmermann J, Reyes-irisarri E, Terwel D, Bulic B, et al. CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer ’ s disease model. J Clin Invest 125(1): 365-78 (2015).
51. Van Beek J, Elward K, Gasque P. Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci 992: 56-71 (2003).
52. Levi-Strauss M, Mallat M. Primary cultures of murine astrocytes produce C3 and factor B, two components of the alternative pathway of complement activation. J Immunol 139(7): 2361-6 (1987).
53. Gasque P, Fontaine M, Morgan BP. Complement expression in human brain. Biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. J Immunol 154(9): 4726-33 (1995).
54. Thomas A, Gasque P, Vaudry D, Gonzalez B, Fontaine M. Expression of a complete and functional complement system by human neuronal cells in vitro. Int Immunol 12(7): 1015-23 (2000).
55. Eikelenboom P, Hack CE, Rozemuller JM, Stam FC. Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Arch B Cell Pathol Incl Mol Pathol 56(4): 259-62 (1989).
56. Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol 154(3): 927-36 (1999).
57. Katsel P, Tan W, Haroutunian V. Gain in brain immunity in the oldest-old differentiates cognitively normal from demented individuals. PLoS One 4(10): e7642 (2009).
58. Wyss-Coray T, Yan F, Lin AH-T, 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(16): 10837-42 (2002).
59. 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(25): 6333-41 (2008).
60. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3): 383-421 (2000).
61. Dinarello CA. Interleukin-1. Cytokine Growth Factor Rev 8(4): 253-65 (1997).
62. Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64(1): 110-22 (2009).
63. Paranjape GS, Gouwens LK, Osborn DC, Nichols MR. Isolated amyloid-β(1-42) protofibrils, but not isolated fibrils, are robust stimulators of microglia. ACS Chem Neurosci 3(4): 302-11 (2012).
64. 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(15): 5709-14 (2000).
65. 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(8): 857-65 (2008).
66. Lamkanfi M, Dixit VM. Mechanisms and Functions of Inflammasomes. Cell 157(5): 1013-22 (2014).
67. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434): 674-8 (2013).
68. Perry RT, Collins JS, Wiener H, Acton R, Go RCP. The role of TNF and its receptors in Alzheimer ’ s disease. Neurobiol Aging 22: 873-83 (2001).
69. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorld Journal 2012; 756357.
70. Mehlhorn G, Hollborn M, Schliebs R. Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int J Dev Neurosci 18(4-5): 423-31 (2000).
71. Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33): 8354-60 (2008).
72. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 178(5): 829-41 (2007).
73. Melik-Parsadaniantz S, Rostene W. Chemokines and neuromodulation. J Neuroimmunol 198(1-2): 62-8 (2008).
74. White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M, et al. Excitatory monocyte chemoattractant protein-1 signaling is upregulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci USA 102(39): 14092-7 (2005).
75. Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, et al. Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat. J Neuroimmunol 56(2): 127-34 (1995).
76. Che X, Ye W, Panga L, Wu DC, Yang GY. Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 902(2): 171-7 (2001).
77. 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(4): 432-8 (2007).
78. Fuhrmann M, Bittner T, Jung CKE, Burgold S, Page RM, Mitteregger G, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13(4): 411-3 (2010).
79. Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am J Pathol 177(5): 2549-62 (2010).
80. Liu B, Hong J-S. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304(1): 1-7 (2003).
81. Ryu JK, Cho T, Choi HB, Wang YT, McLarnon JG. Microglial VEGF receptor response is an integral chemotactic component in Alzheimer’s disease pathology. J Neurosci 29(1): 3-13 (2009).
82. Mclarnon JG. Microglial chemotactic signaling factors in Alzheimer’s disease. Am J Neurodegener Dis 1(3): 199-204 (2012).
83. Burbach GJ, Hellweg R, Haas C A, Del Turco D, Deicke U, Abramowski D, et al. Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J Neurosci 24(10): 2421-30 (2004).
84. Picone P, Nuzzo D, Caruana L, Messina E, Barera A, Vasto S, et al. Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: use of insulin to attenuate metformin’s effect. Biochim Biophys Acta 1853(5): 1046-59 (2015).
85. Han BH, Zhou M-L, Johnson AW, Singh I, Liao F, Vellimana AK, et al. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci USA 112(8): 881-90 (2015).
86. Heneka MT, Wiesinger H, Dumitrescu-Ozimek L, Riederer P, Feinstein DL, Klockgether T. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol 60(9): 906-16 (2001).
87. Vodovotz Y, Lucia MS, Flanders KC, Chesler L, Xie QW, Smith TW, et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med 184(4): 1425-33 (1996).
88. Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, et al. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 71(5): 833-44 (2011).
89. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4): 572-80 (1991).
90. Tancredi V, D’Arcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A, et al. Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 146(2): 176-8 (1992).
91. Lynch MA. What is the biological significance of an age-related increase in IL-1β in hippocampus? Mol Psychiatry 4: 15-8 (1999).
92. Lynch MA. Neuroinflammatory changes negatively impact on LTP: A focus on IL-1β. Brain Res 1-8 (2014).
93. Cunningham C. Microglia and neurodegeneration: The role of systemic inflammation. Glia 61(1): 71-90 (2013).
94. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20(11): 4050-8 (2000).
95. Overk CR, Masliah E. Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease. Biochem Pharmacol 88(4): 508-16 (2014).
96. Walker DG, Dalsing-Hernandez JE, Campbell NA, Lue L-F. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation. Exp Neurol 215(1): 5-19 (2009).
97. Duan R-S, Yang X, Chen Z-G, Lu M-O, Morris C, Winblad B, et al. Decreased fractalkine and increased IP-10 expression in aged brain of APP(swe) transgenic mice. Neurochem Res 33(6): 1085-9 (2008).
98. Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol 16(3): 229-36 (2015).
99. Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord 21(1): 89-93 (2006).
100. Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3): 337-51 (2007).
101. Hommet C, Mondon K, Camus V, Ribeiro MJ, Beaufils E, Arlicot N, et al. Neuroinflammation and β amyloid deposition in Alzheimer’s disease: in vivo quantification with molecular imaging. Dement Geriatr Cogn Disord 37(1-2): 1-18 (2014).
102. Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, et al. Microglia, amyloid, and cognition in Alzheimer’s disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 32(3): 412-9 (2008).
103. Su Z, Herholz K, Gerhard A, Roncaroli F, Du Plessis D, Jackson A, et al. [11C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur J Nucl Med Mol Imaging 40(9): 1406-19 (2013).
104. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. Early report In-vivo measurement of activated microglia in dementia. Lancet Neurol 358: 461-7 (2001).
105. Arlicot N, Tronel C, Bodard S, Garreau L, de la Crompe B, Vandevelde I, et al. Translocator protein (18 kDa) mapping with [125I]-CLINDE in the quinolinic acid rat model of excitotoxicity: a longitudinal comparison with microglial activation, astrogliosis, and neuronal death. Mol Imaging 13(2): 4-11 (2014).
106. O’Brien ER, Kersemans V, Tredwell M, Checa B, Serres S, Soto MS, et al. Glial activation in the early stages of brain metastasis: TSPO as a diagnostic biomarker. J Nucl Med. 55(2): 275-80 (2014).
107. Combs CK. Inflammation and microglia actions in Alzheimer’s disease. J Neuroimmune Pharmacol 4(4): 380-8 (2009).
108. Kummer MP, Vogl T, Axt D, Griep A, Vieira-saecker A, Jessen F, et al. Mrp14 Deficiency Ameliorates Amyloid β Burden by Increasing Microglial Phagocytosis and Modulation of Amyloid Precursor Protein Processing. J Neurosci 32(49): 17824-9 (2012).
109. Ha T-Y, Chang K-A, Kim JA, Kim H-S, Kim S, Chong YH, et al. S100a9 knockdown decreases the memory impairment and the neuropathology in Tg2576 mice, AD animal model. PLoS One 5(1): e8840 (2010).
110. Schilling T, Eder C. Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J Cell Physiol 226(12): 3295-302 (2011).
111. Rangaraju S, Gearing M, Jin L-W, Levey A. Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer’s disease. J Alzheimers Dis 44(3): 797-808 (2015).
112. Streit WJ, Braak H, Xue Q-S, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118(4): 475-85 (2009).
113. Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2(1): a006346 (2012).
114. Paquet C, Amin J, Mouton-Liger F, Nasser M, Love S, Gray F, et al. Effect of active Aβ immunotherapy on neurons in human Alzheimer’s disease. J Pathol 235(5): 721-30 (2014).
115. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63(2): 168-74 (2006).
116. Rodriguez GA, Tai LM, LaDu MJ, Rebeck GW. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J Neuroinflammation 11: 111 (2014).
117. Rosenthal SL, Kamboh MI. Late-onset Alzheimer’s disease genes and the potentially implicated pathways. Curr Genet Med Rep 2: 85-101 (2014).
118. Chan SL, Kim WS, Kwok JB, Hill AF, Cappai R, Rye K-A, et al. ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem 106(2): 793-804 (2008).
119. Kim WS, Li H, Ruberu K, Chan S, Elliott DA, Low JK, et al. Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer’s disease. J Neurosci 33(10): 4387-94 (2013).
120. Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83(1): 11-26 (2014).
121. Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 30(10): 527-35 (2007).
122. Heneka MT, Galea E, Gavriluyk V, Dumitrescu-ozimek L, Daeschner J, Weinberg G, et al. Noradrenergic depletion potentiates β -amyloid-induced cortical inflammation: implications for Alzheimer’s disease. J Neurosci 22(7): 2434-42 (2002).
123. Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, et al. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26(5): 1343-54 (2006).
124. Cui W-Y, Li MD. Nicotinic modulation of innate immune pathways via α7 nicotinic acetylcholine receptor. J Neuroimmune Pharmacol 5(4): 479-88 (2010).
125. Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S, Crayton L, et al. Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer’s disease: assessment of attentional and mnemonic function using CANTAB. Psychopharmacology (Berl) 110(4): 395-401 (1993).
126. Sahakian B, Jones G, Levy R, Gray J, Warburton D. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br J Psychiatry 154: 797-800 (1989).
127. Rezvani AH, Levin ED. Cognitive effects of nicotine. Biol Psychiatry 49(3): 258-67 (2001).
128. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, et al. Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89(2): 337-43 (2004).
129. Duthie A, Chew D, Soiza RL. Non-psychiatric comorbidity associated with Alzheimer’s disease. QJM 104(11): 913-20 (2011).
130. Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 14(1): 133-45 (2003).
131. Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, et al. NOS2 gene deficiency protects from sepsisinduced long-term cognitive deficits. J Neurosci 29(45): 14177-84 (2009).
132. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 462: 453-62 (2007).
133. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Michel J-P, et al. Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 35(2): 410-4 (2004).
134. Jendroska K, Poewe W, Daniel SE, Pluess J, Iwerssen-Schmidt H, Paulsen J, et al. Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol 90(5): 461-6 (1995).
135. Tomimoto H, Wakita H, Akiguchi I, Nakamura S, Kimura J. Temporal profiles of accumulation of amyloid beta/A4 protein precursor in the gerbil after graded ischemic stress. J Cereb Blood Flow Metab 14(4): 565-73 (1994).