Microglial priming and alzheimer’s disease: A possible role for (early) immune challenges and epigenetics?

Frontiers in Human Neuroscience

Volumn 10, Issue , 2016, Pages 15-

  Hoeijmakers, Lianne ^a   Heinen, Yvonne ^a   van Dam, Anne Marie ^b   Lucassen, Paul J ^a   Korosi, Aniko ^a  

^a UNIVERSITY OF AMSTERDAM   (Netherlands)

^b VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Alzheimer s disease; Delirium; Dementia; Immune system; Inflammation; Microglia; Priming

Indexed keywords

CYTOKINE;

AGING; ALZHEIMER DISEASE; BEHAVIOR DISORDER; BRAIN INFECTION; CELL ACTIVATION; CELL ACTIVITY; CELL FUNCTION; COGNITION; COGNITIVE DEFECT; CYTOKINE RELEASE; CYTOKINE RESPONSE; DISEASE COURSE; EPIGENETICS; HUMAN; IMMUNITY; INFLAMMATION; LIFE CYCLE STAGE; MICROGLIA; MICROGLIA PRIMING; PATHOLOGY; PHENOTYPE; REVIEW; UPREGULATION;

EID: 84983757038     PISSN: None     EISSN: 16625161     Source Type: Journal    
DOI: 10.3389/fnhum.2016.00398     Document Type: Review

References (197)

1. Adams-Chapman, I., and Stoll, B. J. (2006). Neonatal infection and long-term neurodevelopmental outcome in the preterm infant. Curr. Opin. Infect. Dis. 19, 290-297. doi: 10.1097/01.qco.0000224825.57976.87
2. Banks, W. A. (2015). The blood-brain barrier in neuroimmunology: tales of separation and assimilation. Brain Behav. Immun. 44, 1-8. doi: 10.1016/j.bbi.2014.08.007
3. Barrientos, R. M., Frank, M. G., Hein, A. M., Higgins, E. A., Watkins, L. R., Rudy, J. W., et al. (2009). Time course of hippocampal IL-1β and memory consolidation impairments in aging rats following peripheral infection. Brain Behav. Immun. 23, 46-54. doi: 10.1016/j.bbi.2008.07.002
4. Barrientos, R. M., Higgins, E. A., Biedenkapp, J. C., Sprunger, D. B., Wright-Hardesty, K. J., Watkins, L. R., et al. (2006). Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol. Aging 27, 723-732. doi: 10.1016/j.neurobiolaging.2005.03.010
5. Barrientos, R. M., Higgins, E. A., Sprunger, D. B., Watkins, L. R., Rudy, J. W., and Maier, S. F. (2002). Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav. Brain Res. 134, 291-298. doi: 10.1016/s0166-4328(02)00043-8
6. Belarbi, K., Jopson, T., Tweedie, D., Arellano, C., Luo, W., Greig, N. H., et al. (2012). TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J. Neuroinflammation 9:23. doi: 10.1186/1742-2094-9-23
7. Ben-Hur, T., Ben-Menachem, O., Furer, V., Einstein, O., Mizrachi-Kol, R., and Grigoriadis, N. (2003). Effects of proinflammatory cytokines on the growth, fate and motility of multipotential neural precursor cells. Mol. Cell. Neurosci. 24, 623-631. doi: 10.1016/s1044-7431(03)00218-5
8. Bilbo, S. D. (2010). Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline. Neurobiol. Learn. Mem. 94, 57-64. doi: 10.1016/j.nlm.2010.04.001
9. Bilbo, S. D., Barrientos, R. M., Eads, A. S., Northcutt, A., Watkins, L. R., Rudy, J. W., et al. (2008). Early-life infection leads to altered BDNF and IL-1β mRNA expression in rat hippocampus following learning in adulthood. Brain Behav. Immun. 22, 451-455. doi: 10.1016/j.bbi.2007.10.003
10. Bilbo, S. D., Biedenkapp, J. C., Der-Evakian, A., Watkins, L. R., Rudy, J. W., and Maier, S. F. (2005a). Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 Inhibition. J. Neurosci. 25, 8000-8009. doi: 10.1523/jneurosci.1748-05.2005
11. Bilbo, S. D., Levkoff, L. H., Mahoney, J. H., Watkins, L. R., Rudy, J. W., and Maier, S. F. (2005b). Neonatal infection induces memory impairments following an immune challenge in adulthood. Behav. Neurosci. 119, 293-301. doi: 10.1037/0735-7044.119.1.293
12. Bilbo, S. D., and Schwarz, J. M. (2009). Early-life programming of later-life brain and behavior: a critical role for the immune system. Front. Behav. Neurosci. 3:14. doi: 10.3389/neuro.08.014.2009
13. Bilbo, S. D., Newsum, N. J., Sprunger, D. B., Watkins, L. R., Rudy, J. W., and Maier, S. F. (2007). Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood. Brain Behav. Immun. 21, 332-342. doi: 10.1016/j.bbi.2006.10.005
14. Bilbo, S. D., Rudy, J. W., Watkins, L. R., and Maier, S. F. (2006). A behavioural characterization of neonatal infection-facilitated memory impairment in adult rats. Behav. Brain Res. 169, 39-47. doi: 10.1016/j.bbr.2005.12.002
15. Billiards, S. S., Haynes, R. L., Folkerth, R. D., Trachtenberg, F. L., Liu, L. G., Volpe, J. J., et al. (2006). Development of microglia in the cerebral white matter of the human fetus and infant. J. Comp. Neurol. 497, 199-208. doi: 10.1002/cne.20991
16. Bizon, J. L., LaSarge, C. L., Montgomery, K. S., McDermott, A. N., Setlow, B., and Griffith, W. H. (2009). Spatial reference and working memory across the lifespan of male Fischer 344 rats. Neurobiol. Aging 30, 646-655. doi: 10.1016/j.neurobiolaging.2007.08.004
17. Bluthé, R. M., Michaud, B., Poli, V., and Dantzer, R. (2000). Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice. Physiol. Behav. 70, 367-373. doi: 10.1016/s0031-9384(00)00269-9
18. Bluthé, R. M., Walter, V., Parnet, P., Layé, S., Lestage, J., Verrier, D., et al. (1994). Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C. R. Acad. Sci. 3 317, 499-503.
19. Bodea, L. G., Wang, Y., Linnartz-Gerlach, B., Kopatz, J., Sinkkonen, L., Musgrove, R., et al. (2014). Neurodegeneration by activation of the microglial complement-phagosome pathway. J. Neurosci. 34, 8546-8556. doi: 10.1523/jneurosci.5002-13.2014
20. Bolton, J. L., and Bilbo, S. D. (2014). Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms. Dialogues Clin. Neurosci. 16, 307-320.
21. Borenstein, A. R., Copenhaver, C. I., and Mortimer, J. A. (2006). Early-life risk factors for alzheimer disease. Alzheimer Dis. Assoc. Disord. 20, 63-72. doi: 10.1097/01.wad.0000201854.62116.d7
22. Brown, A. S., and Derkits, E. J. (2010). Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am. J. Psychiatry 167, 261-280. doi: 10.1176/appi.ajp.2009.09030361
23. Brown, A. S. (2012). Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. Dev. Neurobiol. 72, 1272-1276. doi: 10.1002/dneu.22024
24. Brugg, B., Dubreuil, Y. L., Huber, G., Wollman, E. E., Delhaye-Bouchaud, N., and Mariani, J. (1995). Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proc. Natl. Acad. Sci. U S A 92, 3032-3035. doi: 10.1073/pnas.92.7.3032
25. Bu, X. L., Yao, X. Q., Jiao, S. S., Zeng, F., Liu, Y. H., Xiang, Y., et al. (2015). A study on the association between infectious burden and Alzheimer’s disease. Eur. J. Neurol. 22, 1519-1525. doi: 10.1111/ene.12477
26. Bucks, R. S., Gidron, Y., Harris, P., Teeling, J., Wesnes, K. A., and Perry, V. H. (2008). Selective effects of upper respiratory tract infection on cognition, mood and emotion processing: a prospective study. Brain Behav. Immun. 22, 399-407. doi: 10.1016/j.bbi.2007.09.005
27. Burton, M. D., and Johnson, R. W. (2012). Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning. Brain Behav. Immun. 26, 732-738. doi: 10.1016/j.bbi.2011.10.008
28. Cai, Z., Pan, Z. L., Pang, Y., Evans, O. B., and Rhodes, P. G. (2000). Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr. Res. 47:64. doi: 10.1203/00006450-200001000-00013
29. Camara, M. L., Corrigan, F., Jaehne, E. J., Jawahar, M. C., Anscomb, H., and Baune, B. T. (2015). Effects of centrally administered etanercept on behavior, microglia and astrocytes in mice following a peripheral immune challenge. Neuropsychopharmacology 40, 502-512. doi: 10.1038/npp.2014.199
30. Canani, R. B., Costanzo, M. D., Leone, L., Bedogni, G., Brambilla, P., Cianfarani, S., et al. (2011). Epigenetic mechanisms elicited by nutrition in early life. Nutr. Res. Rev. 24, 198-205. doi: 10.1017/s0954422411000102
31. Cao, M., Cortes, M., Moore, C. S., Leong, S. Y., Durosier, L. D., Burns, P., et al. (2015). Fetal microglial phenotype in vitro carries memory of prior in vivo exposure to inflammation. Front. Cell. Neurosci. 9:294. doi: 10.3389/fncel.2015.00294
32. Castle, S. C. (2000). Clinical relevance of age-related immune dysfunction. Clin. Infect. Dis. 31, 578-585. doi: 10.1086/313947
33. Chakrabarty, P., Li, A., Ceballos-Das, C., Eddy, J. A., Funk, C. C., Moore, B., et al. (2015). IL-10 Alters immunoproteostasis in APP Mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519-533. doi: 10.1016/j.neuron.2014.11.020
34. Chen, J., Buchanan, J. B., Sparkman, N. L., Godbout, J. P., Freund, G. G., and Johnson, R. W. (2008). Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav. Immun. 22, 301-311. doi: 10.1016/j.bbi.2007.08.014
35. Cho, S. H., Chen, J. A., Sayed, F., Ward, M. E., Gao, F., Nguyen, T. A., et al. (2015). SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1. J. Neurosci. 35, 807-818. doi: 10.1523/jneurosci.2939-14.2015
36. Cole, G. M., Lim, G. P., Yang, F., Teter, B., Begum, A., Ma, Q., et al. (2005). Prevention of Alzheimer’s disease: omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol. Aging 26, 133-136. doi: 10.1016/j.neurobiolaging.2005.09.005
37. Cribbs, D. H., Berchtold, N. C., Perreau, V., Coleman, P. D., Rogers, J., Tenner, A. J., et al. (2012). Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J. Neuroinflammation 9:179. doi: 10.1186/1742-2094-9-179
38. Cunningham, C. (2013). Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71-90. doi: 10.1002/glia.22350
39. Cunningham, E. T., Wada, E., Carter, D. B., Tracey, D. E., Battey, J. F., and De Souza, E. B. (1991). Localization of interleukin-1 receptor messenger RNA in murine hippocampus. Endocrinology 128, 2666-2668. doi: 10.1210/endo-128-5-2666
40. Dammann, O., and Leviton, A. (2004). Inflammatory brain damage in preterm newborns-dry numbers, wet lab and causal inferences. Early Hum. Dev. 79, 1-15. doi: 10.1016/j.earlhumdev.2004.04.009
41. Dantzer, R., and Kelley, K. W. (2007). Twenty years of research on cytokine-induced sickness behavior. Brain Behav. Immun. 21, 153-160. doi: 10.1016/j.bbi.2006.09.006
42. Das, S., and Basu, A. (2011). Viral infection and neural stem/progenitor cell’s fate: implications in brain development and neurological disorders. Neurochem. Int. 59, 357-366. doi: 10.1016/j.neuint.2011.02.020
43. Deng, X. H., Bertini, G., Xu, Y. Z., Yan, Z., and Bentivoglio, M. (2006). Cytokine-induced activation of glial cells in the mouse brain is enhanced at an advanced age. Neuroscience 141, 645-661. doi: 10.1016/j.neuroscience.2006.04.016
44. Deverman, B. E., and Patterson, P. H. (2009). Cytokines and CNS development. Neuron 64, 61-78. doi: 10.1016/j.neuron.2009.09.002
45. de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G., and de Vries, J. E. (1991). Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209-1220. doi: 10.1084/jem.174.5.1209
46. Dilger, R. N., and Johnson, R. W. (2008). Aging, microglial cell priming and the discordant central inflammatory response to signals from the peripheral immune system. J. Leukoc. Biol. 84, 932-939. doi: 10.1189/jlb.0208108
47. Dinel, A., Joffre, C., Trifilieff, P., Aubert, A., Foury, A., Le Ruyet, P., et al. (2014). Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood. J. Neuroinflammation 11:155. doi: 10.1186/s12974-014-0155-x
48. Doorn, K. J., Brevé, J. J. P., Drukarch, B., Boddeke, H. W., Huitinga, I., Lucassen, P. J., et al. (2015). Brain region-specific gene expression profiles in freshly isolated rat microglia. Front. Cell. Neurosci. 9:84. doi: 10.3389/fncel.2015.00084
49. Drapeau, E., Mayo, W., Aurousseau, C., Le Moal, M., Piazza, P. V., and Abrous, D. N. (2003). Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl. Acad. Sci. U S A 100, 14385-14390. doi: 10.1073/pnas.2334169100
50. Duggan, P. J., Maalouf, E. F., Watts, T. L., Sullivan, M., Counsell, S. J., Allsop, J., et al. (2001). Intrauterine T-cell activation and increased proinflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet 358, 1699-1700. doi: 10.1016/s0140-6736(01)06723-x
51. Dunn, H. C., Ager, R. R., Baglietto-Vargas, D., Cheng, D., Kitazawa, M., Cribbs, D. H., et al. (2015). Restoration of lipoxin A4 signaling reduces Alzheimer’s disease-like pathology in the 3xTg-AD mouse model. J. Alzheimers Dis. 43, 893-903. doi: 10.3233/JAD-141335
52. Dunn, N., Mullee, M., Perry, V. H., and Holmes, C. (2005). Association between dementia and infectious disease: evidence from a case-control study. Alzheimer Dis. Assoc. Disord. 19, 91-94. doi: 10.1097/01.wad.0000165511.52746.1f
53. Etminan, M., Gill, S., and Samii, A. (2003). Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 327:128. doi: 10.1136/bmj.327.7407.128
54. Farrar, W. L., Kilian, P. L., Ruff, M. R., and Pert, C. B. (1987). Visualization and characterization of inlerukin a receptors in brain. Neuropeptides 139, 459-463.
55. Féart, C., Helmer, C., Fleury, H., Béjot, Y., Ritchie, K., Amouyel, P., et al. (2011). Association between IgM anti-herpes simplex virus and plasma amyloid-beta levels. PLoS One 6:e29480. doi: 10.1371/journal.pone.0029480
56. Feigenson, K. A., Kusnecov, A. W., and Silverstein, S. M. (2014). Inflammation and the two-hit hypothesis of schizophrenia. Neurosci. Biobehav. Rev. 38, 72-93. doi: 10.1016/j.neubiorev.2013.11.006
57. Fenn, A. M., Henry, C. J., Huang, Y., Dugan, A., and Godbout, J. P. (2012). Lipopolysaccharide-induced interleukin (IL)-4 receptor-α expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav. Immun. 26, 766-777. doi: 10.1016/j.bbi.2011.10.003
58. Field, R., Campion, S., Warren, C., Murray, C., and Cunningham, C. (2010). Systemic challenge with the TLR3 agonist poly I: C induces amplified IFNα/β and IL-1β responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav. Immun. 24, 996-1007. doi: 10.1016/j.bbi.2010.04.004
59. Frank, M. G., Barrientos, R. M., Watkins, L. R., and Maier, S. F. (2010). Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo. J. Neuroimmunol. 226, 181-184. doi: 10.1016/j.jneuroim.2010.05.022
60. Garden, G. A. (2013). Epigenetics and the modulation of neuroinflammation. Neurotherapeutics 10, 782-788. doi: 10.1007/s13311-013-0207-4
61. Ghosh, S., Wu, M. D., Shaftel, S. S., Kyrkanides, S., LaFerla, F. M., Olschowka, J. A., et al. (2013). Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J. Neurosci. 33, 5053-5064. doi: 10.1523/JNEUROSCI.4361-12.2013
62. Gibertini, M., Newton, C., Friedman, H., and Klein, T. W. (1995). Spatial learning impairment in mice infected with legionella pneumophila or adminstered exogenous interleukin-1-β. Brain Behav. Immun. 9, 113-128. doi: 10.1006/brbi.1995.1012
63. Gilmore, J. H., Jarskog, L. F., Vadlamudi, S., and Lauder, J. M. (2004). Prenatal infection and risk for schizophrenia: IL-1β, IL-6 and TNFα inhibit cortical neuron dendrite development. Neuropsychopharmacology 29, 1221-1229. doi: 10.1038/sj.npp.1300446
64. Girard, T. D., Jackson, J. C., Pandharipande, P. P., Pun, B. T., Thompson, J. L., Shintani, A. K., et al. (2010). Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit. Care Med. 38, 1513-1520. doi: 10.1097/CCM.0b013e3181e47be1
65. Giulian, D., Young, D. G., Woodward, J., Brown, D. C., and Lachman, L. B. (1988). Interleukin-1 is an astroglial growth factor in the developing brain. J. Neurosci. 8, 709-714.
66. Godbout, J. P., Chen, J., Abraham, J., Richwine, F., Berg, B. M., Kelley, K. W., et al. (2005). Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 19, 1329-1331. doi: 10.1096/fj.05-3776fje
67. Godbout, J. P., Moreau, M., Lestage, J., Chen, J., Sparkman, N. L., Connor, J. O., et al. (2008). Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, 2341-2351. doi: 10.1038/sj.npp.1301649
68. Golan, H., Levav, T., Mendelsohn, A., and Huleihel, M. (2004). Involvement of tumor necrosis factor alpha in hippocampal development and function. Cereb. Cortex 14, 97-105. doi: 10.1093/cercor/bhg108
69. Green, H. F., and Nolan, Y. M. (2014). Inflammation and the developing brain: consequences for hippocampal neurogenesis and behavior. Neurosci. Biobehav. Rev. 40, 1-15. doi: 10.1016/j.neubiorev.2014.01.004
70. Guillot-Sestier, M.-V., Doty, K. R., Gate, D., Rodriguez, J., Leung, B. P., Rezai-Zadeh, K., et al. (2015a). Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85, 534-548. doi: 10.1016/j.neuron.2014.12.068
71. Guillot-Sestier, M.-V., Doty, K. R., and Town, T. (2015b). Innate immunity fights Alzheimer’s disease. Trends Neurosci. 38, 674-681. doi: 10.1016/j.tins.2015.08.008
72. Hagberg, H., Gilland, E., Bona, E., Hanson, L.-Å., Hahn-Zoric, M., Blennow, M., et al. (1996). Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Pediatr. Res. 40, 603-609. doi: 10.1203/00006450-199610000-00015
73. Hagberg, H., Gressens, P., and Mallard, C. (2012). Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann. Neurol. 71, 444-457. doi: 10.1002/ana.22620
74. Hagberg, H., Mallard, C., Ferriero, D. M., Vannucci, S. J., Levison, S. W., Vexler, Z. S., et al. (2015). The role of inflammation in perinatal brain injury. Nat. Rev. Neurol. 11, 192-208. doi: 10.1038/nrneurol.2015.13
75. Harry, G. J. (2013). Microglia during development and aging. Pharmacol. Ther. 139, 313-326. doi: 10.1016/j.pharmthera.2013.04.013
76. Harry, G. J., and Kraft, A. D. (2012). Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 33, 191-206. doi: 10.1016/j.neuro.2012.01.012
77. Hedtjärn, M., Mallard, C., and Hagberg, H. (2004). Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. J. Cereb. Blood Flow Metab. 24, 1333-1351. doi: 10.1097/01.WCB.0000141559.17620.36
78. Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., et al. (2015). Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388-405. doi: 10.1016/S1474-4422(15)70016-5
79. Henry, C. J., Huang, Y., Wynne, A. M., and Godbout, J. P. (2009). Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines. Brain Behav. Immun. 23, 309-317. doi: 10.1016/j.bbi.2008.09.002
80. Heppner, F. L., Ransohoff, R. M., and Becher, B. (2015). Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358-372. doi: 10.1038/nrn3880
81. Hickman, S. E., Allison, E. K., and El Khoury, J. (2008). Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 13, 8354-8360. doi: 10.1523/jneurosci.0616-08.2008
82. Hollingsworth, J. W., Maruoka, S., Boon, K., Garantziotis, S., Li, Z., Tomfohr, J., et al. (2008). In utero supplementation with methyl donors enhances allergic airway disease in mice. J. Clin. Invest. 118, 3462-3469. doi: 10.1172/JCI34378
83. Holmes, C., and Cotterell, D. (2009). Role of infection in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs 23, 993-1002. doi: 10.2165/11310910-000000000-00000
84. Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., et al. (2009). Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768-774. doi: 10.1212/WNL.0b013e3181b6bb95
85. Holmes, C., El-Okl, M., Williams, A., Cunningham, C., Wilcockson, D., and Perry, V. (2003). Systemic infection, interleukin 1β and cognitive decline in Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 74, 788-789. doi: 10.1136/jnnp.74.6.788
86. Holtman, I. R., Raj, D. D., Miller, J. A., Schaafsma, W., Yin, Z., Brouwer, N., et al. (2015). Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3:31. doi: 10.1186/s40478-015-0203-5
87. Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., et al. (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712-716. doi: 10.1126/science.aad8373
88. Hoozemans, J. J. M., Veerhuis, R., Rozemuller, J. M., and Eikelenboom, P. (2006). Neuroinflammation and regeneration in the early stages of Alzheimer’s disease pathology. Int. J. Dev. Neurosci. 24, 157-165. doi: 10.1016/j.ijdevneu.2005.11.001
89. Huang, Y., Henry, C. J., Dantzer, R., Johnson, R. W., and Godbout, J. P. (2008). Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol. Aging 29, 1744-1753. doi: 10.1016/j.neurobiolaging.2007.04.012
90. Itzhaki, R. F., Lathe, R., Balin, B. J., Ball, M. J., Bearer, E. L., Braak, H., et al. (2016). Microbes and Alzheimer’s disease. J. Alzheimers Dis. 51, 979-984. doi: 10.3233/JAD-160152
91. Ivacko, J., Szaflarski, J., Malinak, C., Flory, C., Warren, J. S., and Silverstein, F. S. (1997). Hypoxic-ischemic injury induces monocyte chemoattractant protein-1 expression in neonatal rat brain. J. Cereb. Blood Flow Metab. 17, 759-770. doi: 10.1097/00004647-199707000-00006
92. Jang, S., Dilger, R. N., and Johnson, R. W. (2010). Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J. Nutr. 140, 1892-1898. doi: 10.3945/jn.110.123273
93. Joseph, J. A., Shukitt-Hale, B., and Willis, L. M. (2009). Grape juice, berries and walnuts affect brain aging and behavior. J. Nutr. 139, 1813S-1817S. doi: 10.3945/jn.109.108266
94. Kamer, A. R., Craig, R. G., Pirraglia, E., Dasanayake, A. P., Norman, R. G., Boylan, R. J., et al. (2009). TNF-α and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects. J. Neuroimmunol. 216, 92-97. doi: 10.1016/j.jneuroim.2009.08.013
95. Kannan, V., Brouwer, N., Hanisch, U. K., Regen, T., Eggen, B. J. L., and Boddeke, H. W. G. M. (2013). Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. J. Neurosci. Res. 91, 1133-1142. doi: 10.1002/jnr.23221
96. Kat, M. G., Vreeswijk, R., de Jonghe, J. F. M., van der Ploeg, T., van Gool, W. A., Eikelenboom, P., et al. (2008). Long-term cognitive outcome of delirium in elderly hip surgery patients. a prospective matched controlled study over two and a half years. Dement. Geriatr. Cogn. Disord. 26, 1-8. doi: 10.1159/000140611
97. Kitazawa, M., Cheng, D., Tsukamoto, M. R., Koike, M. A., Wes, P. D., Vasilevko, V., et al. (2011). Blocking IL-1 signaling rescues cognition, attenuates tau pathology and restores neuronal β-catenin pathway function in an Alzheimer’s disease model. J. Immunol. 187, 6539-6549. doi: 10.4049/jimmunol.1100620
98. Kitazawa, M., Medeiros, R., and Laferla, F. M. (2012). Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr. Pharm. Des. 18, 1131-1147. doi: 10.2174/138161212799315786
99. Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., and LaFerla, F. M. (2005). Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J. Neurosci. 25, 8843-8853. doi: 10.1523/JNEUROSCI.2868-05.2005
100. Knuesel, I., Chicha, L., Britschgi, M., Schobel, S. A., Bodmer, M., Hellings, J. A., et al. (2014). Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643-660. doi: 10.1038/nrneurol.2014.187
101. Krstic, D., and Knuesel, I. (2013). Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 9, 25-34. doi: 10.1038/nrneurol.2012.236
102. Krstic, D., Madhusudan, A., Doehner, J., Vogel, P., Notter, T., Imhof, C., et al. (2012). Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflammation 9:151. doi: 10.1186/1742-2094-9-151
103. Külzow, N., Witte, A. V., Kerti, L., Grittner, U., Schuchardt, J. P., Hahn, A., et al. (2016). Impact of omega-3 fatty acid supplementation on memory functions in healthy older adults. J. Alzheimers Dis. 51, 713-725. doi: 10.3233/JAD-150886
104. Kyrkanides, S., Tallents, R. H., Miller, J. H., Olschowka, M. E., Johnson, R., Yang, M., et al. (2011). Osteoarthritis accelerates and exacerbates Alzheimer’s disease pathology in mice. J. Neuroinflammation 8:112. doi: 10.1186/1742-2094-8-112
105. Lahiri, D. K., and Maloney, B. (2010). The “LEARn” (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer’s disease and proposes remedial steps. Exp. Gerontol. 45, 291-296. doi: 10.1016/j.exger.2010.01.001
106. Ledeboer, A., Binnekade, R., Brevé, J. J. P., Bol, J. G. J. M., Tilders, F. J. H., and Van Dam, A. M. (2002). Site-specific modulation of LPS-induced fever and interleukin-1 β expression in rats by interleukin-10. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1762-R1772. doi: 10.1152/ajpregu.00766.2001
107. Lee, C. K., Klopp, R. G., Weindruch, R., and Prolla, T. A. (1999). Gene expression profile of aging and its retardation by caloric restriction. Science 285, 1390-1393. doi: 10.1126/science.285.5432.1390
108. Lee, J. W., Lee, Y. K., Yuk, D. Y., Choi, D. Y., Ban, S. B., Oh, K. W., et al. (2008). Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J. Neuroinflammation 5:37. doi: 10.1186/1742-2094-5-37
109. Lesuis, S. L., Maurin, H., Borghgraef, P., Lucassen, P. J., Van Leuven, F., and Krugers, H. J. (2016). Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer’s disease. Oncotarget doi: 10.18632/oncotarget.9776 [Epub ahead of print].
110. Li, M. D., Burns, T. C., Morgan, A. A., and Khatri, P. (2014). Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases. Acta Neuropathol. Commun. 2:93. doi: 10.1186/s40478-014-0093-y
111. Lim, S. L., Rodriguez-Ortiz, C. J., and Kitazawa, M. (2015). Infection, systemic inflammation and Alzheimer’s disease. Microbes Infect. 17, 549-556. doi: 10.1016/j.micinf.2015.04.004
112. Lin, C.-Y., Chang, Y.-C., Wang, S.-T., Lee, T.-Y., Lin, C.-F., and Huang, C.-C. (2010). Altered inflammatory responses in preterm children with cerebral palsy. Ann. Neurol. 68, 204-212. doi: 10.1002/ana.22049
113. Lindeboom, J., and Weinstein, H. (2004). Neuropsychology of cognitive ageing, minimal cognitive impairment, Alzheimer’s disease and vascular cognitive impairment. Eur. J. Pharmacol. 490, 83-86. doi: 10.1016/j.ejphar.2004.02.046
114. Lindner, M. D. (1997). Reliability, distribution and validity of age-related cognitive deficits in the Morris water maze. Neurobiol. Learn. Mem. 68, 203-220. doi: 10.1006/nlme.1997.3782
115. Liverman, C. S., Kaftan, H. A., Cui, L., Hersperger, S. G., Taboada, E., Klein, R. M., et al. (2006). Altered expression of pro-inflammatory and developmental genes in the fetal brain in a mouse model of maternal infection. Neurosci. Lett. 399, 220-225. doi: 10.1016/j.neulet.2006.01.064
116. Lopez, L. B., Kritz-Silverstein, D., and Barrett-Connor, E. (2011). High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: the rancho bernardo study. J. Nutr. Health Aging 15, 25-31. doi: 10.1007/s12603-011-0009-5
117. Luchsinger, J. A., and Mayeux, R. (2004). Dietary factors and Alzheimer’s disease. Lancet Neurol. 3, 579-587. doi: 10.1016/S1474-4422(04)00878-6
118. Luo, X. G., Ding, J.-Q., and Chen, S.-D. (2010). Microglia in the aging brain: relevance to neurodegeneration. Mol. Neurodegener. 5:12. doi: 10.1186/1750-1326-5-12
119. Lynch, A. M., Walsh, C., Delaney, A., Nolan, Y., Campbell, V. A., and Lynch, M. A. (2004). Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10-a role for IL-1 beta? J. Neurochem. 88, 635-646. doi: 10.1046/j.1471-4159.2003.02157.x
120. Matousek, S. B., Ghosh, S., Shaftel, S. S., Kyrkanides, S., Olschowka, J. A., and O’Banion, M. K. (2012). Chronic IL-1β mediated neuroinflammation mitigates amyloid pathology in a mouse model of alzheimer’s disease without inducing overt neurodegeneration. J. Neuroimmune Pharmacol. 7, 156-164. doi: 10.1007/s11481-011-9331-2
121. Matt, S. M., and Johnson, R. W. (2015). DNA methylation of the IL-1b promoter and associated epigenetic regulators are modulated by immune activation, aging and pharmacological demethylation in primary and BV-2 murine microglia. Brain Behav. Immun. 49:e42. doi: 10.1016/j.bbi.2015.06.158
122. McAlpine, F. E., Lee, J. K., Harms, A. S., Ruhn, K. A., Blurton-Jones, M., Hong, J., et al. (2009). Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol. Dis. 34, 163-177. doi: 10.1016/j.nbd.2009.01.006
123. McGrane, S., Girard, T. D., Thompson, J. L., Shintani, A. K., Woodworth, A., Ely, E. W., et al. (2011). Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients. Crit. Care 15:R78. doi: 10.1186/cc10070
124. Meaney, M. J., Aitken, D. H., van Berkel, C., Bhatnagar, S., and Sapolsky, R. M. (1988). Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 2, 766-768. doi: 10.1126/science.3340858
125. Medeiros, R., Kitazawa, M., Passos, G. F., Baglietto-Vargas, D., Cheng, D., Cribbs, D. H., et al. (2013). Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces alzheimer disease-like pathology in mice. Am. J. Pathol. 182, 1780-1789. doi: 10.1016/j.ajpath.2013.01.051
126. Mehler, M. F., and Kessler, J. A. (1997). Hematolymphopoietic and inflammatory cytokines in neural development. Trends Neurosci. 20, 357-365. doi: 10.1016/s0166-2236(96)01045-4
127. Meldrum, S. J., Strunk, T., Currie, A., Prescott, S. L., Simmer, K., and Whitehouse, A. J. O. (2013). Autism spectrum disorder in children born preterm—role of exposure to perinatal inflammation. Front. Neurosci. 7:123. doi: 10.3389/fnins.2013.00123
128. Meydani, M. (2001). Nutrition interventions in aging and age-associated disease. Ann. N Y Acad. Sci. 928, 226-235. doi: 10.1111/j.1749-6632.2001.tb05652.x
129. Mhatre, S. D., Tsai, C. A., Rubin, A. J., James, M. L., and Andreasson, K. I. (2015). Microglial malfunction: the third rail in the development of Alzheimer’s disease. Trends Neurosci. 38, 621-636. doi: 10.1016/j.tins.2015.08.006
130. Miller, L. C., Isa, S., LoPreste, G., Schaller, J. G., and Dinarello, C. A. (1990). Neonatal interleukin-1 β, interleukin-6 and tumor necrosis factor: cord blood levels and cellular production. J. Pediatr. 117, 961-965. doi: 10.1016/s0022-3476(05)80145-3
131. Miller, D. B., and O’Callaghan, J. P. (2008). Do early-life insults contribute to the late-life development of Parkinson and Alzheimer diseases? Metabolism 57, 44-49. doi: 10.1016/j.metabol.2008.07.011
132. Morris, C. J. (2005). Early-stage and preclinical alzheimer disease. Alzheimer Dis. Assoc. Disord. 19, 163-165. doi: 10.1097/01.wad.0000184005.22611.cc
133. Mosher, K. I., and Wyss-Coray, T. (2014). Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem. Pharmacol. 88, 594-604. doi: 10.1016/j.bcp.2014.01.008
134. Mrak, R. E., and Griffin, W. S. T. (2005). Glia and their cytokines in progression of neurodegeneration. Neurobiol. Aging 26, 349-354. doi: 10.1016/j.neurobiolaging.2004.05.010
135. Murray, C., Sanderson, D. J., Barkus, C., Deacon, R. M. J., Rawlins, J. N. P., Bannerman, D. M., et al. (2012). Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol. Aging 33, 603.e3-616.e3. doi: 10.1016/j.neurobiolaging.2010.04.002
136. Mustafa, M. M., Ramilo, O., Llorens, X. S., Olsen, K. D., Magness, R. R., and McCracken, G. H. (1990). Cerebrospinal fluid prostaglandins, interleukin 1β and tumor necrosis factor in bacterial meningitis. Am. J. Dis. Child. 144, 883-887. doi: 10.1001/archpedi.1990.02150320047024
137. Nayak, D., Roth, T. L., and McGavern, D. B. (2014). Microglia development and function. Annu. Rev. Immunol. 32, 367-402. doi: 10.1146/annurev-immunol-032713-120240
138. Netea, M. G., Joosten, L. A., Latz, E., Mills, K. H., Natoli, G., Stunnenberg, H. G., et al. (2016). Trained immunity: a program of innate immune memory in health and disease. Science 352:aaf1098. doi: 10.1126/science.aaf1098
139. Netea, M. G., Quintin, J., and van der Meer, J. W. M. (2011). Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355-361. doi: 10.1016/j.chom.2011.04.006
140. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318. doi: 10.1126/science.1110647
141. Norden, D. M., and Godbout, J. P. (2013). Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 39, 19-34. doi: 10.1111/j.1365-2990.2012.01306.x
142. O’Connor, T. G., Moynihan, J. A., and Caserta, M. T. (2014). Annual research review: the neuroinflammation hypothesis for stress and psychopathology in children-developmental psychoneuroimmunology. J. Child Psychol. Psychiatry 55, 615-631. doi: 10.1111/jcpp.12187
143. Oitzl, M. S., van Oers, H., Schöbitz, B., and de Kloet, E. R. (1993). Interleukin-1 β, but not interleukin-6, impairs spatial navigation learning. Brain Res. 613, 160-163. doi: 10.1016/0006-8993(93)90468-3
144. O’Shea, T. M., Shah, B., Allred, E. N., Fichorova, R. N., Kuban, K. C. K., Dammann, O., et al. (2013). Inflammation-initiating illnesses, inflammation-related proteins and cognitive impairment in extremely preterm infants. Brain Behav. Immun. 29, 104-112. doi: 10.1016/j.bbi.2012.12.012
145. Paintlia, M. K., Paintlia, A. S., Barbosa, E., Singh, I., and Singh, A. K. (2004). N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J. Neurosci. Res. 78, 347-361. doi: 10.1002/jnr.20261
146. Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., et al. (2011). Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456-1458. doi: 10.1126/science.1202529
147. Plotsky, P. M., and Meaney, M. J. (1993). Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res. Mol. Brain Res. 18, 195-200. doi: 10.1016/0169-328x(93)90189-v
148. Pousset, F. (1994). Developmental expression of cytokine genes in the cortex and hippocampus of the rat central nervous system. Brain Res. Dev. Brain Res. 81, 143-146. doi: 10.1016/0165-3806(94)90078-7
149. Püntener, U., Booth, S., Perry, V. H., and Teeling, J. L. (2012). Long term impact of systemic bacterial infection on the cerebral vasculature and microglia. J. Neuroinflammation 9:146. doi: 10.1186/1742-2094-9-146
150. Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J. S., et al. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453-462. doi: 10.1002/glia.20467
151. Quan, N., and Banks, W. A. (2007). Brain-immune communication pathways. Brain Behav. Immun. 21, 727-735. doi: 10.1016/j.bbi.2007.05.005
152. Querfurth, H. W., and LaFerla, F. M. (2010). Alzheimer’s disease. N. Engl. J. Med. 362, 329-344. doi: 10.1056/NEJMra0909142
153. Rahkonen, T., Luukkainen-Markkula, R., Paanila, S., Sivenius, J., and Sulkava, R. (2000). Delirium episode as a sign of undetected dementia among community dwelling elderly subjects: a 2 year follow up study. J. Neurol. Neurosurg. Psychiatry 69, 519-521. doi: 10.1136/jnnp.69.4.519
154. Ransohoff, R. M., and Perry, V. H. (2009). Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119-145. doi: 10.1146/annurev.immunol.021908.132528
155. Rantakallio, P., Jones, P., Moring, J., and Von Wendt, L. (1997). Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up. Int. J. Epidemiol. 26, 837-843. doi: 10.1093/ije/26.4.837
156. Reemst, K., Lucassen, P. J., and Hol, E. M. (2016). The indispensable roles of microglia and astrocytes during brain development. Front. Hum. Neurosci. in press.
157. Ron-Harel, N., and Schwartz, M. (2009). Immune senescence and brain aging: can rejuvenation of immunity reverse memory loss? Trends Neurosci. 32, 367-375. doi: 10.1016/j.tins.2009.03.003
158. Rubio-Perez, J. M., and Morillas-Ruiz, J. M. (2012). A review: inflammatory process in alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357. doi: 10.1100/2012/756357
159. Rubio-Perez, J. M., and Morillas-Ruiz, J. M. (2012). A review: inflammatory process in alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012:756357. doi: 10.1100/2012/756357
160. Santana, C., Guindeo, M. C., González, G., García-Muñoz, F., Saavedra, P., and Doménech, E. (2001). Cord blood levels of cytokines as predictors of early neonatal sepsis. Acta Paediatr. 90, 1176-1181. doi: 10.1111/j.1651-2227.2001.tb03250.x
161. Schmitz, T., and Chew, L. J. (2008). Cytokines and myelination in the central nervous system. ScientificWorldJournal 8, 1119-1147. doi: 10.1100/tsw.2008.140
162. Schoderboeck, L., Adzemovic, M., Nicolussi, E. M., Crupinschi, C., Hochmeister, S., Fischer, M. T., et al. (2009). The “window of susceptibility” for inflammation in the immature central nervous system is characterized by a leaky blood-brain barrier and the local expression of inflammatory chemokines. Neurobiol. Dis. 35, 368-375. doi: 10.1016/j.nbd.2009.05.026
163. Schwarz, J. M., Hutchinson, M. R., and Bilbo, S. D. (2011). Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 Expression. J. Neurosci. 31, 17835-17847. doi: 10.1523/jneurosci.3297-11.2011
164. Schwarz, J. M., Sholar, P. W., and Bilbo, S. D. (2012). Sex differences in microglial colonization of the developing rat brain. J. Neurochem. 120, 948-963. doi: 10.1111/j.1471-4159.2011.07630.x
165. Sezgin, Z., and Dincer, Y. (2014). Alzheimer’s disease and epigenetic diet. Neurochem. Int. 78, 105-116. doi: 10.1016/j.neuint.2014.09.012
166. Sfera, A., Osorio, C., Price, A. I., Gradini, R., and Cummings, M. (2015). Delirium from the gliocentric perspective. Front. Cell. Neurosci. 9:171. doi: 10.3389/fncel.2015.00171
167. Shaftel, S. S., Kyrkanides, S., Olschowka, J. A., Miller, J. N. H., Johnson, R. E., and O’Banion, M. K. (2007). Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest. 117, 1595-1604. doi: 10.1172/jci31450
168. Shah, F. A., Pike, F., Alvarez, K., Angus, D., Newman, A. B., Lopez, O., et al. (2013). Bidirectional relationship between cognitive function and pneumonia. Am. J. Respir. Crit. Care Med. 188, 586-592. doi: 10.1164/rccm.201212-2154OC
169. Sheng, J. G., Bora, S. H., Xu, G., Borchelt, D. R., Price, D. L., and Koliatsos, V. E. (2003). Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid β peptide in APPswe transgenic mice. Neurobiol. Dis. 14, 133-145. doi: 10.1016/s0969-9961(03)00069-x
170. Sheng, J. G., Mrak, R. E., and Griffin, W. S. T. (1998). Enlarged and phagocytic, but not primed, interleukin-1a-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol. 95, 229-234. doi: 10.1007/s004010050792
171. Sierra, A., Encinas, J. M., Deudero, J. J. P., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., et al. (2010). Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483-495. doi: 10.1016/j.stem.2010.08.014
172. Sierra, A., Gottfried-Blackmore, A. C., McEwen, B. S., and Bulloch, K. (2007). Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55, 412-424. doi: 10.1002/glia.20468
173. Sparkman, N. L., and Johnson, R. W. (2008). Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation 15, 323-330. doi: 10.1159/000156474
174. Spencer, S. J., Heida, J. G., and Pittman, Q. J. (2005). Early life immune challenge—effects on behavioural indices of adult rat fear and anxiety. Behav. Brain Res. 164, 231-238. doi: 10.1016/j.bbr.2005.06.032
175. Strandberg, T. E., Pitkala, K. H., Linnavuori, K., and Tilvis, R. S. (2004). Cognitive impairment and infectious burden in the elderly. Arch. Gerontol. Geriatr. Suppl. 38, 419-423. doi: 10.1016/j.archger.2004.04.053
176. Streit, W. J. (2001). Microglia and macrophages in the developing CNS. Neurotoxicology 22, 619-624. doi: 10.1016/s0161-813x(01)00033-x
177. Streit, W. J., Braak, H., Xue, Q. S., and Bechman, I. (2009). Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 118, 475-485. doi: 10.1007/s00401-009-0556-6
178. Subash, S., Essa, M. M., Al-Asmi, A., Al-Adawi, S., Vaishnav, R., and Guillemin, G. J. (2014). Effect of dietary supplementation of dates in Alzheimer’s disease APPsw/2576 transgenic mice on oxidative stress and antioxidant status. Nutr. Neurosci. 18, 281-289. doi: 10.1179/1476830514Y.0000000134
179. Sy, M., Kitazawa, M., Medeiros, R., Whitman, L., Cheng, D., Lane, T. E., et al. (2011). Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am. J. Pathol. 178, 2811-2822. doi: 10.1016/j.ajpath.2011.02.012
180. Terrando, N., Rei Fidalgo, A., Vizcaychipi, M., Cibelli, M., Ma, D., Monaco, C., et al. (2010). The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit. Care 14:R88. doi: 10.1186/cc9019
181. Uribarri, J., Cai, W., Peppa, M., Goodman, S., Ferrucci, L., Striker, G., et al. (2007). Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress and aging. J. Gerontol. A Biol. Sci. Med. Sci. 62, 427-433. doi: 10.1093/gerona/62.4.427
182. Van Dam, A. M., Bauer, J., Tilders, F. J., and Berkenbosch, F. (1995). Endotoxin-induced appearance of immunoreactive interleukin-1 β in ramified microglia in rat brain: a light and electron microscopic study. Neuroscience 65, 815-826. doi: 10.1016/0306-4522(94)00549-k
183. Van Dam, A. M., Brouns, M., Louisse, S., and Berkenbosch, F. (1992). Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness? Brain Res. 588, 291-296. doi: 10.1016/0006-8993(92)91588-6
184. Van Dam, A. M., De Vries, H. E., Kuiper, J., Zijlstra, F. J., DeBoer, A. G., Tilders, F., et al. (1996). Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune interaction? FASEB J. 10, 351-356.
185. Van den Boogaard, M., Kox, M., Quinn, K. L., van Achterberg, T., van der Hoeven, J. G., Schoonhoven, L., et al. (2011). Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. Crit. Care 15:R297. doi: 10.1186/cc10598
186. Van Gool, W. A., van de Beek, D., and Eikelenboom, P. (2010). Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375, 773-775. doi: 10.1016/s0140-6736(09)61158-2
187. VanGuilder, H. D., Bixler, G. V., Brucklacher, R. M., Farley, J. A., Yan, H., Warrington, J. P., et al. (2011). Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J. Neuroinflammation 8:138. doi: 10.1186/1742-2094-8-138
188. Verreault, R., Laurin, D., Lindsay, J., and De Serres, G. (2001). Past exposure to vaccines and subsequent risk of Alzheimer’s disease. CMAJ 165, 1495-1498.
189. Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., et al. (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90-94. doi: 10.1038/nature10357
190. Vlad, S. C., Miller, D. R., Kowall, N. W., and Felson, D. T. (2008). Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70, 1672-1677. doi: 10.1212/01.wnl.0000311269.57716.63
191. ΔE9 mice: potential mechanism underlying cognitive impairment. Oncotarget doi: 10.18632/oncotarget.8453 [Epub ahead of print].
192. Weaver, I. C. G., Champagne, F. A., Brown, S. E., Dymov, S., Sharma, S., Meaney, M. J., et al. (2005). Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J. Neurosci. 25, 11045-11054. doi: 10.1523/jneurosci.3652-05.2005
193. Wofford, J. L., Loehr, L. R., and Schwartz, E. (1996). Acute cognitive impairment in elderly ED patients: etiologies and outcomes. Am. J. Emerg. Med. 14, 649-653. doi: 10.1016/s0735-6757(96)90080-7
194. Wynne, A. M., Henry, C. J., Huang, Y., Cleland, A., and Godbout, J. P. (2010). Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav. Immun. 24, 1190-1201. doi: 10.1016/j.bbi.2010.05.011
195. Ye, S. M., and Johnson, R. W. (2001). An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9, 183-192. doi: 10.1159/000049025
196. 11C](R)PK11195. J. Cereb. Blood Flow Metab. doi: 10.1177/0271678x16646788 [Epub ahead of print].
197. Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S. M., Iwata, N., Saido, T. C., et al. (2007). Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-351. doi: 10.1016/j.neuron.2007.01.010
198. +T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence. Exp. Gerontol. 38, 981-987. doi: 10.1016/s0531-5565(03)00160-8