Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease

  • Darshpreet Kaur
  • Vivek Sharma
  • Rahul DeshmukhEmail author
Review Article


Alzheimer’s disease (AD) is a neurodegenerative disease that is of high importance to the neuroscience world, yet the complex pathogenicity is not fully understood. Inflammation is usually observed in AD and could implicate both beneficial or detrimental effects depending on the severity of the disease. During initial AD pathology, microglia and astrocyte activation is beneficial since they are involved in amyloid-beta clearance. However, with the progression of the disease, activated microglia elicit detrimental effects by the overexpression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) bringing forth neurodegeneration in the surrounding brain regions. This results in decline in Aβ clearance by microglia; Aβ accumulation thus increases in the brain resulting in neuroinflammation. Thus, Aβ accumulation is the effect of increased release of pro-inflammatory molecules. Reactive astrocytes acquire gain of toxic function and exhibits neurotoxic effects with loss of neurotrophic functions. Astrocyte dysfunctioning results in increased release of cytokines and inflammatory mediators, neurodegeneration, decreased glutamate uptake, loss of neuronal synapses, and ultimately cognitive deficits in AD. We discuss the role of intracellular signaling pathways in the inflammatory responses produced by astrocytes and microglial activation, including the glycogen synthase kinase-3β, nuclear factor kappa B cascade, mitogen-activated protein kinase pathways and c-Jun N-terminal kinase. In this review, we describe the role of neuroinflammation in the chronicity of AD pathogenesis and an overview of the recent research towards the development of new therapies to treat this disorder.


Alzheimer’s disease Microglia Astrocytes Pro-inflammatory cytokines Neuronal synapses Neuroinflammation 



Authors are thankful to the Science and Engineering Board (SERB), Department of Science and Technology, Govt. of India, New Delhi, for providing financial assistance under Fast Track Scheme (DST: SB/YS/LS-111/2013) to Dr. Rahul Deshmukh.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest in this work.


  1. Abe E, Casamenti F, Giovannelli L, Scali C, Pepeu G (1994) Administration of amyloid β-peptides into the medialtum of rats decreases acetylcholine release from hippocampus in vivo. Brain Res 636(1):162–164CrossRefPubMedGoogle Scholar
  2. Abramov AY, Canevari L, Duchen MR (2003) Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23(12):5088–5095CrossRefPubMedGoogle Scholar
  3. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE (2000a) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421CrossRefPubMedPubMedCentralGoogle Scholar
  4. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000b) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421CrossRefPubMedPubMedCentralGoogle Scholar
  5. Aksenov MY, Aksenova MV, Butterfield DA, Hensley K, Vigo-Pelfrey C, Carney JM (1996) Glutamine synthetase-induced enhancement of β-amyloid peptide Aβ (1–40) neurotoxicity accompanied by abrogation of fibril formation and Aβ fragmentation. J Neurochem 66(5):2050–2056CrossRefPubMedGoogle Scholar
  6. Alvarez A, Opazo C, Alarcón R, Garrido J, Inestrosa NC (1997) Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils1. J Mol Biol 272(3):348–361CrossRefPubMedGoogle Scholar
  7. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32(1):1–4CrossRefPubMedGoogle Scholar
  8. Armstrong RA (2009) The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer’s disease. Folia Neuropathol 47(4):289–299PubMedGoogle Scholar
  9. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18(11):1584CrossRefPubMedPubMedCentralGoogle Scholar
  10. Avila-Muñoz E, Arias C (2014) When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer’s disease. Ageing Res Rev 1(18):29–40CrossRefGoogle Scholar
  11. Axelsen PH, Komatsu H, Murray IV (2011) Oxidative stress and cell membranes in the pathogenesis of Alzheimer’s disease. Physiology 26(1):54–69CrossRefPubMedGoogle Scholar
  12. Baik SH, Kang S, Son SM, Mook-Jung I (2016) Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer’s disease mouse model. Glia 64(12):2274–2290CrossRefPubMedGoogle Scholar
  13. Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K (2003) Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci 100(4):2023–2028CrossRefPubMedGoogle Scholar
  14. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V (2009) Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791CrossRefPubMedPubMedCentralGoogle Scholar
  15. Beggiato S, Borelli AC, Ferraro L, Tanganelli S, Antonelli T, Tomasini MC (2018) Palmitoylethanolamide blunts amyloid-β 42-induced astrocyte activation and improves neuronal survival in primary mouse cortical astrocyte-neuron co-cultures. J Alzheimers Dis:1–1 (Preprint)Google Scholar
  16. Belkhelfa M, Rafa H, Medjeber O, Arroul-Lammali A, Behairi N, Abada-Bendib M, Makrelouf M, Belarbi S, Masmoudi AN, Tazir M, Touil-Boukoffa C (2014) IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res 34(11):839–847CrossRefPubMedGoogle Scholar
  17. Bisht K, Sharma K, Tremblay MÈ (2018) Chronic stress as a risk factor for Alzheimer’s disease: roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress. Neurobiol Stress 9:9–21CrossRefPubMedPubMedCentralGoogle Scholar
  18. Boche D, Perry VH, Nicoll JA (2013) Activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39(1):3–18CrossRefPubMedGoogle Scholar
  19. Bouchon A, Dietrich J, Colonna M (2000) Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164(10):4991–4995CrossRefPubMedGoogle Scholar
  20. Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Fish JD, Wyss-Coray T, Buttini M, Mucke L, Mahley RW (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24(10):2527–2534CrossRefPubMedGoogle Scholar
  21. Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH et al (2011) Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement J Alzheimers Assoc 7(4):402–411CrossRefGoogle Scholar
  22. Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol 50(2):534–544CrossRefPubMedPubMedCentralGoogle Scholar
  23. Brugg B, Dubreuil YL, Huber G, Wollman EE, Delhaye-Bouchaud N, Mariani J (1995) Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proc Natl Acad Sci 92(7):3032–3035CrossRefPubMedGoogle Scholar
  24. Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472(7343):319CrossRefPubMedGoogle Scholar
  25. Butterfield DA, Hensley K, Cole P, Subramaniam R, Aksenov M, Aksenova M, Bummer PM, Haley BE, Carney JM (1997) Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer’s disease. J Neurochem 68(6):2451–2457CrossRefPubMedGoogle Scholar
  26. Calsolaro V, Edison P (2016) Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimers Dement 12:719–732CrossRefPubMedGoogle Scholar
  27. Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-l-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53(1):37–46CrossRefPubMedGoogle Scholar
  28. Chang CY, Choi DK, Lee DK, Hong YJ, Park EJ (2013) Resveratrol confers protection against rotenone-induced neurotoxicity by modulating myeloperoxidase levels in glial cells. PLoS One 8(4):e60654CrossRefPubMedPubMedCentralGoogle Scholar
  29. Chiang K, Koo EH (2014) Emerging therapeutics for Alzheimer’s disease. Annu Rev Pharmacol Toxicol 6(54):381–405CrossRefGoogle Scholar
  30. Claycomb KI, Johnson KM, Winokur PN, Sacino AV, Crocker SJ (2013) Astrocyte regulation of CNS inflammation and remyelination. Brain Sci 3(3):1109–1127CrossRefPubMedPubMedCentralGoogle Scholar
  31. Cornejo F, Vruwink M, Metz C, Muñoz P, Salgado N, Poblete J, Andrés ME, Eugenín J, von Bernhardi R (2018) Scavenger receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer’s disease pathophysiology. Brain Behav Immun 1(69):336–350CrossRefGoogle Scholar
  32. Cunningham C, Campion S, Teeling J, Felton L, Perry VH (2007) The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I: C). Brain Behav Immun 21(4):490–502CrossRefPubMedGoogle Scholar
  33. Czeh M, Gressens P, Kaindl AM (2011) The yin and yang of microglia. Dev Neurosci 33(3–4):199–209CrossRefPubMedGoogle Scholar
  34. Dal Prà I, Chiarini A, Armato U (2015) Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer’s disease progression? Neural Regen Res 10(2):213CrossRefGoogle Scholar
  35. Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C (2012) A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet 51(10):681–693CrossRefPubMedGoogle Scholar
  36. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):311–321CrossRefPubMedGoogle Scholar
  37. Dorfman VB, Pasquini L, Riudavets M, López-Costa JJ, Villegas A, Troncoso JC, Lopera F, Castaño EM, Morelli L (2010) Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer’s disease. Neurobiol Aging 31(10):1743–1757CrossRefPubMedGoogle Scholar
  38. Duthey B (2013) Background paper 6.11: Alzheimer disease and other dementias. Public Health Approach Innovat 20:1–74Google Scholar
  39. Falcão AS, Silva RF, Pancadas S, Fernandes A, Brito MA, Brites D (2007) Apoptosis and impairment of neurite network by short exposure of immature rat cortical neurons to unconjugated bilirubin increase with cell differentiation and are additionally enhanced by an inflammatory stimulus. J Neurosci Res 85(6):1229–1239CrossRefPubMedGoogle Scholar
  40. Farlow MR, Brosch JR (2013) Immunotherapy for Alzheimer’s disease. Neurol Clin 31(3):869–878CrossRefPubMedGoogle Scholar
  41. Fayuk D, Yakel JL (2005) Ca2 + permeability of nicotinic acetylcholine receptors in rat hippocampal CA1 interneurones. The Journal of physiology. 566(3):759–768CrossRefPubMedPubMedCentralGoogle Scholar
  42. Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, Abner EL, Petersen RC, Federoff HJ, Miller BL, Goetzl EJ (2015) Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement 11(6):600–607CrossRefPubMedGoogle Scholar
  43. Folch J, Petrov D, Ettcheto M, Abad S, Sánchez-López E, García ML, Olloquequi J, Beas-Zarate C, Auladell C, Camins A (2016) Current research therapeutic strategies for Alzheimer’s disease treatment. Neural Plast. 2016:8501693. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105CrossRefPubMedGoogle Scholar
  45. Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND, Weiner HL, El Khoury J (2013) Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 25(4):2030CrossRefGoogle Scholar
  46. Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM (2012) Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 32(46):16129–16140CrossRefPubMedPubMedCentralGoogle Scholar
  47. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011) Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2(6):e167CrossRefPubMedPubMedCentralGoogle Scholar
  48. Garwood C, Faizullabhoy A, Wharton SB, Ince PG, Heath PR, Shaw PJ, Baxter L, Gelsthorpe C, Forster G, Matthews FE, Brayne C (2013) Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 39(7):788–799CrossRefPubMedGoogle Scholar
  49. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF (2006) Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res 81(1):47–63CrossRefPubMedGoogle Scholar
  50. Godyń J, Jończyk J, Panek D, Malawska B (2016) Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep 68(1):127–138CrossRefPubMedGoogle Scholar
  51. Gomez-Nicola D, Perry VH (2015) Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neurosci 21(2):169–184Google Scholar
  52. Grienberger C, Rochefort NL, Adelsberger H, Henning HA, Hill DN, Reichwald J, Staufenbiel M, Konnerth A (2012) Stagedline of neuronal function in vivo in an animal model of Alzheimer’s disease. Nat Commun 10(3):774CrossRefGoogle Scholar
  53. Griffin WS, Stanley LC, Ling CH, White L, MacLeod V, Perrot LJ, White C, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in down syndrome and Alzheimer disease. Proc Natl Acad Sci 86(19):7611–7615CrossRefPubMedGoogle Scholar
  54. Griffin WS, Sheng JG, Roberts GW, Mrak RE (1995) Interleukin-1 expression in different plaque types in Alzheimer’s disease: significance in plaque evolution. J Neuropathol Exp Neurol 54(2):276–281CrossRefPubMedGoogle Scholar
  55. Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE (1998) Glial-neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’in disease progression. Brain Pathol 8(1):65–72CrossRefPubMedGoogle Scholar
  56. Griffin WS, Liu L, Li Y, Mrak RE, Barger SW (2006) Interleukin-1 mediates Alzheimer and Lewy body pathologies. J Neuroinflamm 3(1):5CrossRefGoogle Scholar
  57. Grolla AA, Fakhfouri G, Balzaretti G, Marcello E, Gardoni F, Canonico PL, DiLuca M, Genazzani AA, Lim D (2013a) Aβ leads to Ca2 + signaling alterations and transcriptional changes in glial cells. Neurobiol Aging 34(2):511–522CrossRefPubMedGoogle Scholar
  58. Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A (2013b) Amyloid-β and Alzheimer’s disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4(5):e623CrossRefPubMedPubMedCentralGoogle Scholar
  59. Hampel H, Ewers M, Burger K, Annas P, Mortberg A, Bogstedt A, Frolich L, Schroder J, Schonknecht P, Riepe MW, Kraft I (2009) Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 70(6):922CrossRefPubMedGoogle Scholar
  60. Hane FT, Robinson M, Lee BY, Bai O, Leonenko Z, Albert MS (2017) Recent progress in Alzheimer’s disease research, part 3: diagnosis and treatment. J Alzheimers Dis 57(3):645–665CrossRefPubMedPubMedCentralGoogle Scholar
  61. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184CrossRefPubMedGoogle Scholar
  62. Hashioka S, Klegeris A, McGeer PL (2012) Inhibition of human astrocyte and microglia neurotoxicity by calcium channel blockers. Neuropharmacology 63(4):685–691CrossRefPubMedGoogle Scholar
  63. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674CrossRefPubMedGoogle Scholar
  64. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405CrossRefPubMedPubMedCentralGoogle Scholar
  65. Hertz L, Dringen R, Schousboe A, Robinson SR (1999) Astrocytes: glutamate producers for neurons. J Neurosci Res 57(4):417–428CrossRefPubMedGoogle Scholar
  66. Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33):8354–8360CrossRefPubMedPubMedCentralGoogle Scholar
  67. Hill JM, Lukiw WJ (2015) Microbial-generated amyloids and Alzheimer’s disease (AD). Front Aging Neurosci 10(7):9Google Scholar
  68. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E (2008) Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. The Lancet. 372(9634):216–223CrossRefGoogle Scholar
  69. Hong HS, Hwang EM, Sim HJ, Cho HJ, Boo JH, Oh SS, Kim SU, Mook-Jung I (2003) Interferon γ stimulates β-secretase expression and sAPPβ production in astrocytes. Biochem Biophys Res Commun 307(4):922–927CrossRefPubMedGoogle Scholar
  70. Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P (2006) Neuroinflammation and regeneration in the early stages of Alzheimer’s disease pathology. Int J Dev Neurosci 24(2–3):157–165CrossRefPubMedGoogle Scholar
  71. Huang Y (2010) Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med 16(6):287–294CrossRefPubMedGoogle Scholar
  72. Jaturapatporn D, Isaac MGEKN, McCleery J, Tabet N (2012) Aspirin steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database of Syst Rev. CrossRefGoogle Scholar
  73. Jay TR, Von Saucken VE, Landreth GE (2017) TREM2 in neurodegenerative diseases. Mol Neurodegen 12(1):56CrossRefGoogle Scholar
  74. Jazvinšćak JM, Hof PR, Šimić G (2015) Ceramides in Alzheimer’s disease: key mediators of neuronal apoptosis induced by oxidative stress and Aβ accumulation. Oxid Med Cell longev 2015:346783Google Scholar
  75. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M, Gutierrez A, Vitorica J (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28(45):11650–11661CrossRefPubMedGoogle Scholar
  76. Jucker M (2010) The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med 16(11):1210CrossRefPubMedGoogle Scholar
  77. Kar S, Slowikowski SP, Westaway D, Mount HT (2004) Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci 29:427–441PubMedPubMedCentralGoogle Scholar
  78. Karran E, Mercken M, De Strooper B (2011a) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discovery 10(9):698CrossRefPubMedGoogle Scholar
  79. Karran E, Mercken M, De Strooper B (2011b) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698CrossRefPubMedGoogle Scholar
  80. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373CrossRefPubMedGoogle Scholar
  81. Khan MS, Ali T, Kim MW, Jo MH, Chung JI, Kim MO (2018) Anthocyanins improve hippocampus-dependent memory function and prevent neurodegeneration via JNK/Akt/GSK3β signaling in LPS-treated adult mice. Mol Neurobiol 19:1–7Google Scholar
  82. Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226(10):2484–2493CrossRefPubMedPubMedCentralGoogle Scholar
  83. Kim C, Ho DH, Suk JE, You S, Michael S, Kang J, Lee SJ, Masliah E, Hwang D, Lee HJ, Lee SJ (2013) Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun 5(4):1562CrossRefGoogle Scholar
  84. Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM (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(12):6539–6549CrossRefPubMedPubMedCentralGoogle Scholar
  85. Koistinaho M, Lin S, Wu XI, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nat Med 10(7):719CrossRefPubMedGoogle Scholar
  86. Korvatska O, Leverenz JB, Jayadev S, McMillan P, Kurtz I, Guo X, Rumbaugh M, Matsushita M, Girirajan S, Dorschner MO, Kiianitsa K (2015) R47H variant of TREM2 associated with Alzheimer disease in a large late-onset family: clinical, genetic, and neuropathological study. JAMA Neurol 72(8):920–927CrossRefPubMedPubMedCentralGoogle Scholar
  87. Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, Manalastas A, Hilfiker M, Pfister S, Schwerdel C, Riether C (2012) Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflamm 9(1):1CrossRefGoogle Scholar
  88. Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323(5918):1211–1215CrossRefPubMedPubMedCentralGoogle Scholar
  89. Kumar A, Seghal N, Padi SV, Naidu PS (2006a) Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats. Eur J Pharmacol 551(1–3):58–66CrossRefPubMedGoogle Scholar
  90. Kumar A, Seghal N, Padi SV, Naidu PS (2006b) Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats. Eur J Pharmacol 551(1–3):58–66CrossRefPubMedGoogle Scholar
  91. Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, König S, Roeber S, Jessen F (2011) Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron 71(5):833–844CrossRefPubMedGoogle Scholar
  92. LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3(11):862CrossRefPubMedGoogle Scholar
  93. LaFerla FM, Oddo S (2005) Alzheimer’s disease: Aβ, tau and synaptic dysfunction. Trends Mol Med 11(4):170–176CrossRefPubMedGoogle Scholar
  94. Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflügers Arch Eur J Physiol 460(2):525–542CrossRefGoogle Scholar
  95. Le Prince G, Delaere P, Fages C, Lefrançois T, Touret M, Salanon M, Tardy M (1995) Glutamine synthetase (GS) expression is reduced in senile dementia of the Alzheimer type. Neurochem Res 20(7):859–862CrossRefPubMedGoogle Scholar
  96. Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, Lee K, Cho WG, Jung JK, Han SB, Han JY (2012) Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflamm 9(1):35Google Scholar
  97. Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ (2011) Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 31(18):6627–6638CrossRefPubMedPubMedCentralGoogle Scholar
  98. Lim D, Iyer A, Ronco V, Grolla AA, Canonico PL, Aronica E, Genazzani AA (2013) Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB. Glia. 61(7):1134–1145CrossRefPubMedGoogle Scholar
  99. Linnartz B, Wang Y, Neumann H (2010) Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation. Int J Alzheimer’s Dis. CrossRefGoogle Scholar
  100. Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS (2001) Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. J Neurochem 77(1):182–189CrossRefPubMedGoogle Scholar
  101. Liu C, Cui G, Zhu M, Kang X, Guo H (2014) Neuroinflammation in Alzheimer’s disease: chemokines produced by astrocytes and chemokine receptors. Int J Clin Exp Pathol 7(12):8342PubMedPubMedCentralGoogle Scholar
  102. Liu H, Deng Y, Gao J, Liu Y, Shi J, Gong Q (2015) Sodium hydrosulfide attenuates beta-amyloid-induced cognitive deficits and neuroinflammation via modulation of MAPK/NF-κB pathway in rats. Curr Alzheimer Res 12(7):673–683CrossRefPubMedGoogle Scholar
  103. López-González I, Schlüter A, Aso E, Garcia-Esparcia P, Ansoleaga B, Llorens F, Carmona M, Moreno J, Fuso A, Portero-Otin M, Pamplona R (2015) Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species. J Neuropathol Exp Neurol 74(4):319–344CrossRefPubMedGoogle Scholar
  104. Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64(1):110–122CrossRefPubMedPubMedCentralGoogle Scholar
  105. Lukiw WJ, Bazan NG (2000) Neuroinflammatory signaling upregulation in Alzheimer’s disease. Neurochem Res 25(9–10):1173–1184CrossRefPubMedGoogle Scholar
  106. Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W (2012) Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123(1):224–235CrossRefPubMedPubMedCentralGoogle Scholar
  107. Markesbery WR, Lovell MA (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging 19(1):33–36CrossRefPubMedGoogle Scholar
  108. Masliah E, Hansen L, Alford M, Deteresa R, Mallory M (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40(5):759–766CrossRefPubMedGoogle Scholar
  109. Mathiesen C, Brazhe A, Thomsen K, Lauritzen M (2013) Spontaneous calcium waves in Bergman glia increase with age and hypoxia and reduce tissue oxygen. J Cereb Blood Flow Metab 33(2):161–169CrossRefPubMedGoogle Scholar
  110. McGeer EG, McGeer PL (1997) Inflammatory cytokines in the CNS. CNS Drugs 7(3):214–228CrossRefGoogle Scholar
  111. McGeer PL, McGeer EG (2013) The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 126(4):479–497CrossRefPubMedGoogle Scholar
  112. McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79(1–2):195–200CrossRefPubMedGoogle Scholar
  113. McGeer PL, Schulzer M, McGeer EG (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease. A review of 17 epidemiologic studies. Neurology 47(2):425–432CrossRefPubMedGoogle Scholar
  114. Melis V, Magbagbeolu M, Rickard JE, Horsley D, Davidson K, Harrington KA, Goatman K, Goatman EA, Deiana S, Close SP, Zabke C (2015) Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol 26(4):353CrossRefPubMedPubMedCentralGoogle Scholar
  115. Menting KW, Claassen JA (2014) β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front Aging Neurosci 21(6):165Google Scholar
  116. Meraz RIOSMA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J, Campos-Peña V (2013) Inflammatory process in Alzheimer’s disease. Front Integr Neurosci 13(7):59Google Scholar
  117. Morris GP, Clark IA, Vissel B (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun 2(1):135PubMedPubMedCentralGoogle Scholar
  118. Mouri A, Zou LB, Iwata N, Saido TC, Wang D, Wang MW, Noda Y, Nabeshima T (2006) Inhibition of neprilysin by thiorphan (icv) causes an accumulation of amyloid β and impairment of learning and memory. Behav Brain Res 168(1):83–91CrossRefPubMedGoogle Scholar
  119. Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971(2):197–209CrossRefPubMedGoogle Scholar
  120. Pannasch U, Rouach N (2013) Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci 36(7):405–417CrossRefPubMedGoogle Scholar
  121. Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, Mizuno T, Suzumura A (2012) GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J Neuroinflamm 9(1):268CrossRefGoogle Scholar
  122. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M (2012) Glial cells in (patho) physiology. J Neurochem 121(1):4–27CrossRefPubMedPubMedCentralGoogle Scholar
  123. Parvathenani LK, Tertyshnikova S, Greco CR, Roberts SB, Robertson B, Posmantur R (2003) P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J Biol Chem 278(15):13309–13317CrossRefPubMedGoogle Scholar
  124. Paula-Lima AC, Brito-Moreira J, Ferreira ST (2013) Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer’s disease. J Neurochem 126(2):191–202CrossRefPubMedGoogle Scholar
  125. Pihlaja R, Koistinaho J, Kauppinen R, Sandholm J, Tanila H, Koistinaho M (2011) Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes. Glia 59(11):1643–1657CrossRefPubMedGoogle Scholar
  126. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462CrossRefPubMedPubMedCentralGoogle Scholar
  127. Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7(3):137CrossRefPubMedPubMedCentralGoogle Scholar
  128. Riera J, Hatanaka R, Uchida T, Ozaki T, Kawashima R (2011) Quantifying the uncertainty of spontaneous Ca 2 + oscillations in astrocytes: particulars of Alzheimer’s disease. Biophys J 101(3):554–564CrossRefPubMedPubMedCentralGoogle Scholar
  129. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, de LIano SR (2010) 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. The Lancet Neurol 9(4):363–372CrossRefPubMedGoogle Scholar
  130. Rodriguez JJ, Olabarria M, Chvatal A, Verkhratsky A (2009) Astroglia in dementia and Alzheimer’s disease. Cell Death Differ 16(3):378CrossRefPubMedGoogle Scholar
  131. Rodriguez-Perez AI, Borrajo A, Rodriguez-Pallares J, Guerra MJ, Labandeira-Garcia JL (2015) Interaction between NADPH-oxidase and Rho-kinase in angiotensin II-induced microglial activation. Glia 63(3):466–482CrossRefPubMedGoogle Scholar
  132. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW et al (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43(8):1609–1611CrossRefPubMedGoogle Scholar
  133. Rossi D (2015) Astrocyte physiopathology: at the crossroads of intercellular networking, inflammation and cell death. Prog Neurobiol 1(130):86–120CrossRefGoogle Scholar
  134. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3):675–686CrossRefPubMedGoogle Scholar
  135. Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. Sci World J 2012:756357. CrossRefGoogle Scholar
  136. Rudy CC, Hunsberger HC, Weitzner DS, Reed MN (2015) The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer’s disease. Aging Dis 6(2):131CrossRefPubMedPubMedCentralGoogle Scholar
  137. Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodríguez-Rodríguez E, de Munain AL, de Pancorbo MM, Pérez-Tur J, Álvarez V, Antonell A, López-Arrieta J (2014) Assessing the role of the TREM2 p. R47H variant as a risk factor for Alzheimer’s disease and frontotemporal dementia. Neurobiol Aging 35(2):444CrossRefPubMedGoogle Scholar
  138. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, Van Dyck CH, Mulnard R (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73(24):2061–2070CrossRefPubMedPubMedCentralGoogle Scholar
  139. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, Hall GF (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287(6):3842–3849CrossRefPubMedGoogle Scholar
  140. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, Van Leuven F, Heneka MT (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretase. J Neurosci 23(30):9796–9804CrossRefPubMedGoogle Scholar
  141. Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J (2006) Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ. Proc Natl Acad Sci 103(2):443–448CrossRefPubMedGoogle Scholar
  142. Scuderi C, Stecca C, Iacomino A, Steardo L (2013a) Role of astrocytes in major neurological disorders: the evidence and implications. IUBMB Life 65(12):957–961CrossRefPubMedGoogle Scholar
  143. Scuderi C, Stecca C, Iacomino A, Steardo L (2013b) Role of astrocytes in major neurological disorders: the evidence and implications. IUBMB Life 65(12):957–961CrossRefPubMedGoogle Scholar
  144. Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT (2011) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179(3):1373–1384CrossRefPubMedPubMedCentralGoogle Scholar
  145. Serrano-Pozo A, Muzikansky A, Gómez-Isla T, Growdon JH, Betensky RA, Frosch MP, Hyman BT (2013) Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol 72(6):462–471CrossRefPubMedPubMedCentralGoogle Scholar
  146. Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4(5):E131CrossRefPubMedGoogle Scholar
  147. Shrivastava AN, Kowalewski JM, Renner M, Bousset L, Koulakoff A, Melki R, Giaume C, Triller A (2013) β-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors. Glia 61(10):1673–1686CrossRefPubMedGoogle Scholar
  148. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Investig 122(3):787–795CrossRefPubMedGoogle Scholar
  149. Siddique H, Hynan LS, Weiner MF (2009) Effect of a serotonin reuptake inhibitor on irritability, apathy and psychotic symptoms in patients with Alzheimer’s disease. J Clin Psychiatry 70(6):915CrossRefPubMedPubMedCentralGoogle Scholar
  150. Šimić G, Babić Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, Bažadona D, Buée L, De Silva R, Di Giovanni G, Wischik C (2016) Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 6(1):6CrossRefPubMedPubMedCentralGoogle Scholar
  151. Slattery CF, Beck JA, Harper L, Adamson G, Abdi Z, Uphill J, Campbell T, Druyeh R, Mahoney CJ, Rohrer JD, Kenny J (2014) R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia. Alzheimers Dement 10(6):602–608CrossRefPubMedGoogle Scholar
  152. Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci 88(23):10540–10543CrossRefPubMedGoogle Scholar
  153. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32(12):638–647CrossRefPubMedPubMedCentralGoogle Scholar
  154. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35CrossRefPubMedGoogle Scholar
  155. Stack C, Jainuddin S, Elipenahli C, Gerges M, Starkova N, Starkov AA, Jové M, Portero-Otin M, Launay N, Pujol A, Kaidery NA (2014) Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet 23(14):3716–3732CrossRefPubMedPubMedCentralGoogle Scholar
  156. Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiat 68(10):930–941CrossRefPubMedGoogle Scholar
  157. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4):647–657CrossRefPubMedPubMedCentralGoogle Scholar
  158. Tan Ü, Kutlu NP (1991) The distribution of paw preference in right-, left-, and mixed pawed male and female cats: the role of a female right-shift factor in handedness. Int J Neurosci 59(4):219–229CrossRefPubMedGoogle Scholar
  159. Tarkowski E, Andreasen N, Tarkowski A, Blennow K (2003) Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74(9):1200–1205CrossRefPubMedPubMedCentralGoogle Scholar
  160. Tong G, Castaneda L, Wang JS, Sverdlov O, Huang SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C (2012) Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men. Clinical Drug Invest 32(11):761–769CrossRefGoogle Scholar
  161. Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 37(2):289–305CrossRefPubMedGoogle Scholar
  162. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science 291(5504):657–661CrossRefPubMedGoogle Scholar
  163. Van den Kommer TN, Dik MG, Comijs HC, Jonker C, Deeg DJ (2010) Homocysteine and inflammation: predictors of cognitiveline in older persons? Neurobiol Aging 31(10):1700–1709CrossRefPubMedGoogle Scholar
  164. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7(4):399–412CrossRefPubMedPubMedCentralGoogle Scholar
  165. Vodovotz Y, Lucia MS, Flanders KC, Chesler L, Xie QW, Smith TW et al (1996) Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J Exp Med 184:1425–1433. CrossRefPubMedGoogle Scholar
  166. Vollmar P, Kullmann JS, Thilo B, Claussen MC, Rothhammer V, Jacobi H, Sellner J, Nessler S, Korn T, Hemmer B (2010) Active immunization with amyloid-β 1–42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. J Immunol 13:1001765Google Scholar
  167. Wan Y, Xu J, Meng F, Bao Y, Ge Y, Lobo N, Vizcaychipi MP, Zhang D, Gentleman SM, Maze M, Ma D (2010) Cognitiveline following major surgery is associated with gliosis, β-amyloid accumulation, and τ phosphorylation in old mice. Crit Care Med 38(11):2190–2198CrossRefPubMedGoogle Scholar
  168. Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A, Mayer-Proschel M, Bieberich E (2012) Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4) potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 287(25):21384–21395CrossRefPubMedPubMedCentralGoogle Scholar
  169. Wang C, Nie X, Zhang Y, Li T, Mao J, Liu X, Gu Y, Shi J, Xiao J, Wan C, Wu Q (2015) Reactive oxygen species mediate nitric oxide production through ERK/JNK MAPK signaling in HAPI microglia after PFOS exposure. Toxicol Appl Pharmacol 288(2):143–151CrossRefPubMedGoogle Scholar
  170. Wang HY, Trocmé-Thibierge C, Stucky A, Shah SM, Kvasic J, Khan A, Morain P, Guignot I, Bouguen E, Deschet K, Pueyo M (2017) Increased Aβ 42-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer’s disease pathogenesis. Alzheimers Res Ther 9(1):54CrossRefPubMedPubMedCentralGoogle Scholar
  171. Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 23(5):88Google Scholar
  172. Wegiel J, Wang KC, Tarnawski M, Lach B (2000) Microglial cells are the driving force in fibrillar plaque formation, whereas astrocytes are a leading factor in plaque degradation. Acta Neuropathol 100(4):356–364CrossRefPubMedGoogle Scholar
  173. Wilcock GK, Gauthier S, Frisoni GB, Jia J, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Schelter BO, Wischik DJ, Davis CS (2018) Potential of low dose leuco-methylthioninium bis (hydromethanesulphonate)(LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary outcome in a phase III clinical trial. J Alzheimer’s Dis, pp 1–24 (Preprint) Google Scholar
  174. Willard B, Hauss-Wegrzyniak B, Wenk GL (1999) Pathological and biochemical consequences of acute and chronic neuroinflammation within the basal forebrain cholinergic system of rats. Neuroscience 88(1):193–200CrossRefPubMedGoogle Scholar
  175. Willis M, Kaufmann WA, Wietzorrek G, Hutter-Paier B, Moosmang S, Humpel C, Hofmann F, Windisch M, Günther Knaus H, Marksteiner J (2010) L-type calcium channel Ca V 1.2 in transgenic mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670 M/N671L) mutations. J Alzheimers Dis 20(4):1167–1180CrossRefPubMedGoogle Scholar
  176. Wilson RS, Segawa E, Boyle PA, Anagnos SE, Hizel LP, Bennett DA (2012) The natural history of cognitiveline in Alzheimer’s disease. Psychol Aging 27(4):1008CrossRefPubMedPubMedCentralGoogle Scholar
  177. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM (2012) Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 11(7):597–604CrossRefPubMedGoogle Scholar
  178. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12(9):1005PubMedGoogle Scholar
  179. Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2(1):a006346CrossRefPubMedPubMedCentralGoogle Scholar
  180. Xia M, Qin S, Wu L, Mackay CR, Hyman BT (1998) Immunohistochemical study of the β-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol 153(1):31–37CrossRefPubMedPubMedCentralGoogle Scholar
  181. Zhao Y, Zhao B (2013) Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell longev 25:2013Google Scholar
  182. Zhao H, Wang SL, Qian L, Jin JL, Li H, Xu Y, Zhu XL (2013) Diammonium glycyrrhizinate attenuates Aβ1–42-induced neuroinflammation and regulates MAPK and NF-κB pathways in vitro and in vivo. CNS Neurosci Ther 19(2):117–124CrossRefPubMedGoogle Scholar
  183. Zhao Y, Dua P, Lukiw WJ (2015) Microbial sources of amyloid and relevance to amyloidogenesis and Alzheimer’s disease (AD). Journal of Alzheimer’s disease & Parkinsonism. 5(1):177Google Scholar
  184. Zhao Y, Jaber V, Lukiw WJ (2017) Secretory products of the human gi tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol 11(7):318CrossRefGoogle Scholar
  185. Zhu D, Lai Y, Shelat PB, Hu C, Sun GY, Lee JC (2006) Phospholipases A2 mediate amyloid-β peptide-induced mitochondrial dysfunction. J Neurosci 26(43):11111–11119CrossRefPubMedGoogle Scholar
  186. Zhu B, Wang ZG, Ding J, Liu N, Wang DM, Ding LC, Yang C (2014) Chronic lipopolysaccharide exposure induces cognitive dysfunction without affecting BDNF expression in the rat hippocampus. Exp Ther Med 7(3):750–754CrossRefPubMedPubMedCentralGoogle Scholar
  187. Zhu S, Wang J, Zhang Y, He J, Kong J, Wang JF, Li XM (2017) The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS 1 transgenic mouse model of Alzheimer’s disease. CNS Neurosci Ther 23(4):310–320CrossRefPubMedGoogle Scholar
  188. Zou LB, Mouri A, Iwata N, Saido TC, Wang D, Wang MW, Mizoguchi H, Noda Y, Nabeshima T (2006) Inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid β and impairment of learning and memory. J Pharmacol Exp Ther 317(1):334–340CrossRefPubMedGoogle Scholar
  189. Zou J, Wang YX, Dou FF, Lü HZ, Ma ZW, Lu PH, Xu XM (2010) Glutamine synthetase down-regulation reduces astrocyte protection against glutamate excitotoxicity to neurons. Neurochem Int 56(4):577–584CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences and TechnologyMaharaja Ranjit Singh Punjab Technical UniversityBathindaIndia
  2. 2.Government College of PharmacyShimlaIndia

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