Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer’s Disease

Author(s): Evi Paouri , Spiros Georgopoulos * .

Journal Name: Current Alzheimer Research

Volume 16 , Issue 6 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


After years of failed therapeutic attempts targeting beta-amyloid (Aβ) in AD, there is now increasing evidence suggesting that inflammation holds a pivotal role in AD pathogenesis and immune pathways can possibly comprise primary therapeutic targets. Inflammation is a key characteristic of numerous diseases including neurodegenerative disorders and thus not surprisingly suppression of inflammation frequently constitutes a major therapeutic strategy for a wide spectrum of disorders. Several brain-resident and peripherally-derived immune populations and inflammatory mediators are involved in AD pathophysiology, with microglia comprising central cellular player in the disease process. Systemic inflammation, mostly in the form of infections, has long been observed to induce behavioral alterations and cognitive dysfunction, suggesting for a close interaction of the peripheral immune system with the brain. Systemic inflammation can result in neuroinflammation, mainly exhibited as microglial activation, production of inflammatory molecules, as well as recruitment of peripheral immune cells in the brain, thus shaping a cerebral inflammatory milieu that may seriously impact neuronal function. Increasing clinical and experimental studies have provided significant evidence that acute (e.g. infections) or chronic (e.g. autoimmune diseases like rheumatoid arthritis) systemic inflammatory conditions may be associated with increased AD risk and accelerate AD progression. Here we review the current literature that links systemic with CNS inflammation and the implications of this interaction for AD in the context of acute and chronic systemic pathologies as acute infection and rheumatoid arthritis. Elucidating the mechanisms that govern the crosstalk between the peripheral and the local brain immune system may provide the ground for new therapeutic approaches that target the immune-brain interface and shed light on the understanding of AD.

Keywords: Alzheimer's disease, systemic inflammation, peripheral inflammation, neuroinflammation, neurodegeneration, microglia, TNF-α, rheumatoid arthritis.

Selkoe D, Mandelkow E, Holtzman D. Deciphering Alzheimer disease. Cold Spring Harb Perspect Med 2(1)a011460 (2012)
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63(3): 287-303. (2009)
Bertram L, Tanzi RE. Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9(10): 768-78. (2008)
Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 68(2): 270-81. (2010)
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580): 353-6. (2002)
Neve RL, Robakis NK. Alzheimer’s disease: a re-examination of the amyloid hypothesis. Trends Neurosci 21(1): 15-9. (1998)
Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci 30(45): 14946-54. (2010)
Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18(6): 794-9. (2015)
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 100(6): 1527-32. (2018)
Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6): 358-72. (2015)
Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 18(6): 800-6. (2015)
Iacono D, Volkmann I, Nennesmo I, Pedersen NL, Fratiglioni L, Johansson B, et al. Same ages, same genes: same brains, same pathologies?: dementia timings, co-occurring brain pathologies, apoe genotypes in identical and fraternal age-matched twins at autopsy. Alzheimer Dis Assoc Disord 30(2): 178-82. (2016)
Maloney B, Lahiri DK. Epigenetics of dementia: understanding the disease as a transformation rather than a state. Lancet Neurol 15(7): 760-74. (2016)
Lahiri DK, Maloney B, Zawia NH. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 14(11): 992-1003. (2009)
Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 353(6301): 777-83. (2016)
Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest 122(4): 1164-71. (2012)
Meyer-Luehmann M, Prinz M. Myeloid cells in Alzheimer’s disease: culprits, victims or innocent bystanders? Trends Neurosci 38(10): 659-68. (2015)
Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 20(2): 136-44. (2017)
Town T, Tan J, Flavell RA, Mullan M. T-cells in Alzheimer’s disease. Neuromol Med 7(3): 255-64. (2005)
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)
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)
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3): 707-20. (2013)
Eikelenboom P, Hoozemans JJ, Veerhuis R, van Exel E, Rozemuller AJ, van Gool WA. Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer’s disease. Alzheimers Res Ther 4(3): 15. (2012)
Morris JK, Honea RA, Vidoni ED, Swerdlow RH, Burns JM. Is Alzheimer’s disease a systemic disease? Biochim Biophys Acta 1842(9): 1340-9. (2014)
Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol 9(1): 25-34. (2013)
Cunningham C, Hennessy E. Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimers Res Ther 7(1): 33. (2015)
Goldeck D, Witkowski JM, Fulop T, Pawelec G. Peripheral Immune Signatures in Alzheimer Disease. Curr Alzheimer Res 13(7): 739-49. (2016)
Wotton CJ, Goldacre MJ. Associations between specific autoimmune diseases and subsequent dementia: retrospective record-linkage cohort study, UK. J Epidemiol Community Health 71(6): 576-83. (2017)
Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 327(7407): 128. (2003)
Shadfar S, Hwang CJ, Lim MS, Choi DY, Hong JT. Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents. Arch Pharm Res 38(12): 2106-19. (2015)
Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, et al. Anti-inflammatory drugs and risk of Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis 44(2): 385-96. (2015)
McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47(2): 425-32. (1996)
Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for rheumatoid arthritis and risk of alzheimer’s disease: a nested case-control analysis. CNS Drugs 30(11): 1111-20. (2016)
Decourt B, Lahiri DK, Sabbagh MN. Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease. Curr Alzheimer Res 14(4): 412-25. (2017)
Camargo CHF, Justus FF, Retzlaff G, Blood MRY, Schafranski MD. Action of anti-TNF-alpha drugs on the progression of Alzheimer’s disease: a case report. Dement Neuropsychol 9(2): 196-200. (2015)
Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 5: 2. (2008)
Li Q, Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18(4): 225-42. (2018)
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)
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726): 1314-8. (2005)
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29(13): 3974-80. (2009)
Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron 77(1): 10-8. (2013)
Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med 3(9): 1018-27. (2017)
Greenhalgh AD, Zarruk JG, Healy LM, Baskar Jesudasan SJ, Jhelum P, Salmon CK, et al. Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury. PLoS Biol 16(10)e2005264 (2018)
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)
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4): 388-405. (2015)
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimers Dement 12(6): 719-32. (2016)
Fiala M, Zhang L, Gan X, Sherry B, Taub D, Graves MC, et al. Amyloid-beta induces chemokine secretion and monocyte migration across a human blood--brain barrier model. Mol Med 4(7): 480-9. (1998)
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)
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)
Sastre M, Walter J, Gentleman SM. Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 5: 25. (2008)
Wang W-Y, Tan M-S, Yu J-T, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10): 136. (2015)
Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39(1): 19-34. (2013)
Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35(5): 601-12. (2013)
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet 49(9): 1373-84. (2017)
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, 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)
Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43(5): 436-41. (2011)
Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10): 1094-9. (2009)
Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, et al. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67(12): 1473-84. (2010)
Li JT, Zhang Y. TREM2 regulates innate immunity in Alzheimer’s disease. J Neuroinflammation 15(1): 107. (2018)
Korvatska O, Leverenz JB, Jayadev S, McMillan P, Kurtz I, Guo X, et al. R47H variant of trem2 associated with Alzheimer disease in a large late-onset family: clinical, genetic, and neuropathological study. JAMA Neurol 72(8): 920-7. (2015)
Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, et al. The microglial innate immune receptor trem2 is required for synapse elimination and normal brain connectivity. Immunity 48(5): 979-91-e8. (2018)
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90(4): 724-39. (2016)
Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, et al. Apolipoprotein E Is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290(43): 26043-50. (2015)
Grathwohl SA, Kalin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, et al. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12(11): 1361-3. (2009)
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139(Pt 4): 1265-81. (2016)
Varvel NH, Grathwohl SA, Degenhardt K, Resch C, Bosch A, Jucker M, et al. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-beta deposition in mouse models of Alzheimer’s disease. J Exp Med 212(11): 1803-9. (2015)
Sosna J, Philipp S, Albay R III, Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM, et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol Neurodegener 13(1): 11. (2018)
Goldmann T, Wieghofer P, Jordao MJ, Prutek F, Hagemeyer N, Frenzel K, et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 17(7): 797-805. (2016)
Bechmann I, Galea I, Perry VH. What is the blood-brain barrier (not)? Trends Immunol 28(1): 5-11. (2007)
Galea I, Palin K, Newman TA, Van Rooijen N, Perry VH, Boche D. Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain. Glia 49(3): 375-84. (2005)
Kim WK, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J, et al. CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 168(3): 822-34. (2006)
Bechmann I, Priller J, Kovac A, Bontert M, Wehner T, Klett FF, et al. Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14(10): 1651-8. (2001)
Williams K, Alvarez X, Lackner AA. Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia 36(2): 156-64. (2001)
Faraco G, Park L, Anrather J, Iadecola C. Brain perivascular macrophages: characterization and functional roles in health and disease. J Mol Med (Berl) 95(11): 1143-52. (2017)
Hawkes CA, McLaurin J. Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci USA 106(4): 1261-6. (2009)
Mildner A, Schlevogt B, Kierdorf K, Bottcher C, Erny D, Kummer MP, et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci 31(31): 11159-71. (2011)
Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pistik R, et al. Brain perivascular macrophages initiate the neurovascular dysfunction of alzheimer abeta peptides. Circ Res 121(3): 258-69. (2017)
Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ. Astrocytes in Alzheimer’s disease. Neurotherapeutics 7(4): 399-412. (2010)
Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, et al. Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8(1): 67-80. (2011)
Van Eldik LJ, Carrillo MC, Cole PE, Feuerbach D, Greenberg BD, Hendrix JA, et al. The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimers Dement (N Y) 2(2): 99-109. (2016)
Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9(4): 453-7. (2003)
Pihlaja R, Koistinaho J, Kauppinen R, Sandholm J, Tanila H, Koistinaho M. Multiple cellular and molecular mechanisms are involved in human Abeta clearance by transplanted adult astrocytes. Glia 259(11): 1643-57. (2011)
Saido T, Leissring MA. Proteolytic degradation of amyloid beta-protein. Cold Spring Harb Perspect Med 2(6)a006379 (2012)
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4(147)147ra11 (2012)
Mrak RE, Griffinbc WS. The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer’s disease. Neurobiol Aging 22(6): 915-22. (2001)
Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia 58(3): 300-14. (2010)
Moynagh PN. The interleukin-1 signalling pathway in astrocytes: a key contributor to inflammation in the brain. J Anat 207(3): 265-9. (2005)
Weiner HL, Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5): 404-16. (2006)
Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B. Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol Dis 7(6 Pt B): 682-9. (2000)
Rodriguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323: 170-82. (2016)
Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC, et al. Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood-brain barrier. Eur J Clin Invest 32(5): 360-71. (2002)
Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S, et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 21(8): 880-6. (2015)
Baik SH, Cha MY, Hyun YM, Cho H, Hamza B, Kim DK, et al. Migration of neutrophils targeting amyloid plaques in Alzheimer’s disease mouse model. Neurobiol Aging 35(6): 1286-92. (2014)
Hickman SE, El Khoury J. Mechanisms of mononuclear phagocyte recruitment in Alzheimer’s disease. CNS Neurol Disord Drug Targets 9(2): 168-73. (2010)
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)
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(6): 681-7. (2008)
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(4): 489-502. (2006)
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(1): 134-42. (2005)
Lebson L, Nash K, Kamath S, Herber D, Carty N, Lee DC, et al. Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice. J Neurosci 30(29): 9651-8. (2010)
Koistinaho M, Koistinaho J. Interactions between Alzheimer’s disease and cerebral ischemia--focus on inflammation. Brain Res Brain Res Rev 48(2): 240-50. (2005)
Algotsson A, Winblad B. The integrity of the blood-brain barrier in Alzheimer’s disease. Acta Neurol Scand 115(6): 403-8. (2007)
Bowman GL, Kaye JA, Moore M, Waichunas D, Carlson NE, Quinn JF. Blood-brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology 68(21): 1809-14. (2007)
Bien-Ly N, Boswell CA, Jeet S, Beach TG, Hoyte K, Luk W, et al. Lack of widespread bbb disruption in alzheimer’s disease models: focus on therapeutic antibodies. Neuron 88(2): 289-97. (2015)
Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients. J Alzheimers Dis 7(3): 221-32. (2005) discussion 55-62.
Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, et al. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer’s disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci USA 104(31): 12849-54. (2007)
Zaghi J, Goldenson B, Inayathullah M, Lossinsky AS, Masoumi A, Avagyan H, et al. Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy. Acta Neuropathol 117(2): 111-24. (2009)
Avagyan H, Goldenson B, Tse E, Masoumi A, Porter V, Wiedau-Pazos M, et al. Immune blood biomarkers of Alzheimer disease patients. J Neuroimmunol 210(1-2): 67-72. (2009)
Sollvander S, Ekholm-Pettersson F, Brundin RM, Westman G, Kilander L, Paulie S, et al. Increased number of plasma b cells producing autoantibodies against abeta42 protofibrils in Alzheimer’s disease. J Alzheimers Dis 48(1): 63-72. (2015)
Monsonego A, Nemirovsky A, Harpaz I. CD4 T cells in immunity and immunotherapy of Alzheimer’s disease. Immunology 139(4): 438-46. (2013)
Mietelska-Porowska A, Wojda U. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers. J Immunol Res 20174626540 (2017)
Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol 124(1-2): 83-92. (2002)
Fisher Y, Nemirovsky A, Baron R, Monsonego A. Dendritic cells regulate amyloid-beta-specific T-cell entry into the brain: the role of perivascular amyloid-beta. J Alzheimers Dis 27(1): 99-111. (2011)
Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9(4): 339-49. (1988)
Monsonego A, Imitola J, Zota V, Oida T, Weiner HL. Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells. J Immunol 171(5): 2216-24. (2003)
McQuillan K, Lynch MA, Mills KHG. Activation of mixed glia by Aβ-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain Behav Immun 24(4): 598-607. (2010)
Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain 139(Pt 4): 1237-51. (2016)
Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat Commun 6: 7967. (2015)
Domingues C, da Cruz ESOAB, Henriques AG. Impact of cytokines and chemokines on alzheimer’s disease neuropathological hallmarks. Curr Alzheimer Res 14(8): 870-82. (2017)
Zheng C, Zhou XW, Wang JZ. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-alpha, TGF-beta and IFN-gamma. Transl Neurodegener 5: 7. (2016)
Azizi G, Khannazer N, Mirshafiey A. The potential role of chemokines in alzheimer’s disease pathogenesis. Am J Alzheimers Dis Other Demen 29(5): 415-25. (2014)
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(6): 1595-604. (2007)
Cherry JD, Olschowka JA, O’Banion MK. Arginase 1+ microglia reduce Abeta plaque deposition during IL-1beta-dependent neuroinflammation. J Neuroinflammation 12: 203. (2015)
Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, et al. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 24(2): 548-59. (2010)
Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, et al. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci 33(11): 5053-64. (2013)
Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, et al. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model. J Immunol 187(12): 6539-49. (2011)
Chakrabarty P, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine TNFalpha results in attenuation of amyloid deposition in vivo. Mol Neurodegener 6: 16. (2011)
Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 173(6): 1768-82. (2008)
Gabbita SP, Johnson MF, Kobritz N, Eslami P, Poteshkina A, Varadarajan S, et al. Oral TNFalpha modulation alters neutrophil infiltration, improves cognition and diminishes tau and amyloid pathology in the 3xTgAD mouse model. PLoS One 10(10)e0137305 (2015)
He P, Cheng X, Staufenbiel M, Li R, Shen Y. Long-term treatment of thalidomide ameliorates amyloid-like pathology through inhibition of beta-secretase in a mouse model of Alzheimer’s disease. PLoS One 8(2)e55091 (2013)
McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 34(1): 163-77. (2009)
Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, et al. Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 1368: 239-47. (2011)
Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, et al. Tumor necrosis factor-alpha synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J Neuroinflammation 9: 106. (2012)
Paouri E, Tzara O, Zenelak S, Georgopoulos S. Genetic deletion of tumor necrosis factor-alpha attenuates amyloid-beta production and decreases amyloid plaque formation and glial response in the 5XFAD model of Alzheimer’s disease. J Alzheimers Dis 60(1): 165-81. (2017)
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)
Jiang H, He P, Xie J, Staufenbiel M, Li R, Shen Y. Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IkappaBalpha. Hum Mol Genet 23(18): 4906-18. (2014)
Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, Knowlden SA, Wright TW, et al. Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-alpha suppressive therapeutic strategies in the brain. Am J Pathol 179(4): 2053-70. (2011)
Montgomery SL, Narrow WC, Mastrangelo MA, Olschowka JA, O’Banion MK, Bowers WJ. Chronic neuron- and age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloid- and Tau-related pathologies. Am J Pathol 182(6): 2285-97. (2013)
Sankowski R, Mader S, Valdes-Ferrer SI. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci 9: 28. (2015)
Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 18(5): 407-13. (2004)
Quan N, Banks WA. Brain-immune communication pathways. Brain Behav Immun 21(6): 727-35. (2007)
Holmes C. Review: systemic inflammation and Alzheimer’s disease. Neuropathol Appl Neurobiol 39(1): 51-68. (2013)
Balusu S, Van Wonterghem E, De Rycke R, Raemdonck K, Stremersch S, Gevaert K, et al. Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles. EMBO Mol Med 8(10): 1162-83. (2016)
Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 27(12): 1892-900. (2001)
Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 291(14): 1753-62. (2004)
Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304(16): 1787-94. (2010)
Sharshar T, Carlier R, Bernard F, Guidoux C, Brouland J-P, Nardi O, et al. Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 33(5): 798-806. (2007)
Shah DK, Doyle LW, Anderson PJ, Bear M, Daley AJ, Hunt RW, et al. adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term. J Pediatr 153(2): 170-5.e1. (2008)
Lemstra AW. Groen in't Woud JC, Hoozemans JJ, van Haastert ES, Rozemuller AJ, Eikelenboom P, et al Microglia activation in sepsis: a case-control study. J Neuroinflam 4(1): 4. (2007)
Munster BC, Aronica E, Zwinderman AH, Eikelenboom P, Cunningham C, Rooij SE. Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation Res 14(6): 615-22. (2011)
Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 61(1): 71-90. (2013)
Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 12: 114. (2015)
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5): 453-62. (2007)
Terrando N, Rei Fidalgo A, Vizcaychipi M, Cibelli M, Ma D, Monaco C, et al. The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care 14(3): R88. (2010)
Kondo S, Kohsaka S, Okabe S. Long-term changes of spine dynamics and microglia after transient peripheral immune response triggered by LPS in vivo. Mol Brain 4: 27. (2011)
Anderson ST, Commins S, Moynagh PN, Coogan AN. Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse. Brain Behav Immun 43: 98-109. (2015)
Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, et al. NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci 29(45): 14177-84. (2009)
Griffin EW, Skelly DT, Murray CL, Cunningham C. Cyclooxygenase-1-dependent prostaglandins mediate susceptibility to systemic inflammation-induced acute cognitive dysfunction. J Neurosci 33(38): 15248-58. (2013)
Riazi K, Galic MA, Kentner AC, Reid AY, Sharkey KA, Pittman QJ. Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J Neurosci 35(12): 4942-52. (2015)
Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA 105(44): 17151-6. (2008)
Paouri E, Tzara O, Kartalou GI, Zenelak S, Georgopoulos S. Peripheral tumor necrosis factor-alpha (TNF-alpha) modulates amyloid pathology by regulating blood-derived immune cells and glial response in the brain of AD/TNF transgenic mice. J Neurosci 37(20): 5155-71. (2017)
Fuggle NR, Howe FA, Allen RL, Sofat N. New insights into the impact of neuro-inflammation in rheumatoid arthritis. Front Neurosci 8: 357. (2014)
Teeling JL, Carare RO, Glennie MJ, Perry VH. Intracerebral immune complex formation induces inflammation in the brain that depends on Fc receptor interaction. Acta Neuropathol 124(4): 479-90. (2012)
Polfliet MM, Goede PH, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD, van den Berg TK. A method for the selective depletion of perivascular and meningeal macrophages in the central nervous system. J Neuroimmunol 116(2): 188-95. (2001)
Serrats J, Schiltz JC, Garcia-Bueno B, van Rooijen N, Reyes TM, Sawchenko PE. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65(1): 94-106. (2010)
D’Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci 29(7): 2089-102. (2009)
Banks WA, Robinson SM. Minimal penetration of lipopolysaccharide across the murine blood-brain barrier. Brain Behav Immun 24(1): 102-9. (2010)
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatics. Nature 523(7560): 337-41. (2015)
Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol 4(4): 462-75. (2009)
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immun (2016)
Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, et al. Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav Immun 23(4): 507-17. (2009)
Erickson MA, Hartvigson PE, Morofuji Y, Owen JB, Butterfield DA, Banks WA. Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. J Neuroinflammation 9: 150. (2012)
Weintraub MK, Kranjac D, Eimerbrink MJ, Pearson SJ, Vinson BT, Patel J, et al. Peripheral administration of poly I:C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse. Behav Brain Res 266: 183-7. (2014)
Ujiie M, Dickstein DL, Carlow DA, Jefferies WA. Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10(6): 463-70. (2003)
Suhara T, Magrane J, Rosen K, Christensen R, Kim HS, Zheng B, et al. Abeta42 generation is toxic to endothelial cells and inhibits eNOS function through an Akt/GSK-3beta signaling-dependent mechanism. Neurobiol Aging 24(3): 437-51. (2003)
Hayashi S, Sato N, Yamamoto A, Ikegame Y, Nakashima S, Ogihara T, et al. Alzheimer disease-associated peptide, amyloid beta40, inhibits vascular regeneration with induction of endothelial autophagy. Arterioscler Thromb Vasc Biol 29(11): 1909-15. (2009)
Takeda S, Sato N, Takeuchi D, Kurinami H, Shinohara M, Niisato K, et al. Angiotensin receptor blocker prevented beta-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling. Hypertension 54(6): 1345-52. (2009)
Takeda S, Sato N, Ikimura K, Nishino H, Rakugi H, Morishita R. Increased blood-brain barrier vulnerability to systemic inflammation in an Alzheimer disease mouse model. Neurobiol Aging 34(8): 2064-70. (2013)
Raj DD, Moser J, van der Pol SM, van Os RP, Holtman IR, Brouwer N, et al. Enhanced microglial pro-inflammatory response to lipopolysaccharide correlates with brain infiltration and blood-brain barrier dysregulation in a mouse model of telomere shortening. Aging Cell 14(6): 1003-13. (2015)
Nee LE, Lippa CF. Alzheimer’s disease in 22 twin pairs--13-year follow-up: hormonal, infectious and traumatic factors. Dement Geriatr Cogn Disord 10(2): 148-51. (1999)
Dunn N, Mullee M, Perry VH, Holmes C. Association between dementia and infectious disease: evidence from a case-control study. Alzheimer Dis Assoc Disord 19(2): 91-4. (2005)
Koyama A, O’Brien J, Weuve J, Blacker D, Metti AL, Yaffe K. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: a meta-analysis. J Gerontol A Biol Sci Med Sci 68(4): 433-40. (2013)
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73(10): 768-74. (2009)
Licastro F, Carbone I, Raschi E, Porcellini E. The 21st century epidemic: infections as inductors of neuro-degeneration associated with Alzheimer’s Disease. Immun Ageing 11(1): 22. (2014)
Lim SL, Rodriguez-Ortiz CJ, Kitazawa M. Infection, systemic inflammation, and Alzheimer’s disease. Microbes Infect 17(8): 549-56. (2015)
Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, et al. A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol 22(12): 1519-25. (2015)
Tilvis RS, Kahonen-Vare MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE. Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci 59(3): 268-74. (2004)
Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, et al. Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Arch Neurol 61(5): 668-72. (2004)
Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 52(2): 168-74. (2002)
Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, et al. Inflammatory markers and the risk of Alzheimer disease: the Framingham Study. Neurology 68(22): 1902-8. (2007)
Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 13: 1359. (2007)
Fong TG, Jones RN, Shi P, Marcantonio ER, Yap L, Rudolph JL, et al. Delirium accelerates cognitive decline in Alzheimer disease. Neurology 72(18): 1570-5. (2009)
Kat MG, Vreeswijk R, de Jonghe JF, van der Ploeg T, van Gool WA, Eikelenboom P, et al. 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): 1-8. (2008)
Brugg B, Dubreuil YL, Huber G, Wollman EE, Delhaye-Bouchaud N, Mariani J. Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proc Natl Acad Sci USA 92(7): 3032-5. (1995)
Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 5: 37. (2008)
Kahn MS, Kranjac D, Alonzo CA, Haase JH, Cedillos RO, McLinden KA, et al. Prolonged elevation in hippocampal Abeta and cognitive deficits following repeated endotoxin exposure in the mouse. Behav Brain Res 229(1): 176-84. (2012)
Hauss-Wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL. Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Res 780(2): 294-303. (1998)
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)
Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. 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(39): 8843-53. (2005)
Sly LM, Krzesicki RF, Brashler JR, Buhl AE, McKinley DD, Carter DB, et al. Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer’s disease. Brain Res Bull 56(6): 581-8. (2001)
Ziegler-Heitbrock HW. Molecular mechanism in tolerance to lipopolysaccharide. J Inflamm 45(1): 13-26. (1995)
Faggioni R, Fantuzzi G, Villa P, Buurman W, van Tits LJ, Ghezzi P. Independent down-regulation of central and peripheral tumor necrosis factor production as a result of lipopolysaccharide tolerance in mice. Infect Immun 63(4): 1473-7. (1995)
Puntener U, Booth SG, Perry VH, Teeling JL. Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. J Neuroinflammation 9: 146. (2012)
Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation 9: 151. (2012)
McManus RM, Higgins SC, Mills KH, Lynch MA. Respiratory infection promotes T cell infiltration and amyloid-beta deposition in APP/PS1 mice. Neurobiol Aging 35(1): 109-21. (2014)
Bradley JR. TNF-mediated inflammatory disease. J Pathol 214(2): 49-60. (2008)
Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2(8657): 244-7. (1989)
Butler DM, Maini RN, Feldmann M, Brennan FM. Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. Eur Cytokine Netw 6(4): 225-30. (1995)
Piguet PF, Grau GE, Vesin C, Loetscher H, Gentz R, Lesslauer W. Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 77(4): 510-4. (1992)
Thorbecke GJ, Shah R, Leu CH, Kuruvilla AP, Hardison AM, Palladino MA. Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci USA 89(16): 7375-9. (1992)
Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci USA 89(20): 9784-8. (1992)
Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 10(13): 4025-31. (1991)
Shealy DJ, Wooley PH, Emmell E, Volk A, Rosenberg A, Treacy G, et al. Anti-TNF-alpha antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Res 4(5): R7. (2002)
Jacobs AH, Tavitian B. Noninvasive molecular imaging of neuroinflammation. J Cereb Blood Flow Metab 32(7): 1393-415. (2012)
Nishioku T, Furusho K, Tomita A, Ohishi H, Dohgu S, Shuto H, et al. Potential role for S100A4 in the disruption of the blood-brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis. Neuroscience 189: 286-92. (2011)
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 376(9746): 1094-108. (2010)
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42(3 Pt 1): 631-9. (1992)
Nagy Z, Esiri MM, Jobst KA, Morris JH, King EM, McDonald B, et al. Relative roles of plaques and tangles in the dementia of Alzheimer’s disease: correlations using three sets of neuropathological criteria. Dementia 6(1): 21-31. (1995)
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)
Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, et al. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 84(21): 2161-8. (2015)
Park SM, Shin JH, Moon GJ, Cho SI, Lee YB, Gwag BJ. Effects of collagen-induced rheumatoid arthritis on amyloidosis and microvascular pathology in APP/PS1 mice. BMC Neurosci 12: 106. (2011)
Xu WD, Firestein GS, Taetle R, Kaushansky K, Zvaifler NJ. Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J Clin Invest 83(3): 876-82. (1989)
Boyd TD, Bennett SP, Mori T, Governatori N, Runfeldt M, Norden M, et al. GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimers Dis 21(2): 507-18. (2010)
Kyrkanides S, Tallents RH, Miller JN, Olschowka ME, Johnson R, Yang M, et al. Osteoarthritis accelerates and exacerbates Alzheimer’s disease pathology in mice. J Neuroinflammation 8: 112. (2011)
Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology 38(11): 1682-7. (1988)
Davis DG, Schmitt FA, Wekstein DR, Markesbery WR. Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58(4): 376-88. (1999)
Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, et al. Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96(6): 3228-33. (1999)
Saito T, Matsuba Y, Yamazaki N, Hashimoto S, Saido TC. Calpain activation in Alzheimer’s model mice is an artifact of APP and presenilin overexpression. J Neurosci 36(38): 9933-6. (2016)
Robakis NK. Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging 32(3): 372-9. (2011)

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [559 - 574]
Pages: 16
DOI: 10.2174/1567205016666190321154618
Price: $58

Article Metrics

PDF: 42