Immune attack: the role of inflammation in Alzheimer disease (original) (raw)

• Wimo, A. & Prince, M. World Alzheimer Report 2010: The Global Economic Impact of Dementia (Alzheimer's Disease International (ADI), 2010).
  Google Scholar
• Querfurth, H. W. & LaFerla, F. M. Alzheimer's disease. N. Engl. J. Med. 362, 329–344 (2010).
  Article CAS PubMed Google Scholar
• Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
  CAS PubMed Google Scholar
• Prokop, S., Miller, K. R. & Heppner, F. L. Microglia actions in Alzheimer's disease. Acta Neuropathol. 126, 461–477 (2013).
  Article CAS PubMed Google Scholar
• Gandy, S. & Heppner, F. L. Microglia as dynamic and essential components of the amyloid hypothesis. Neuron 78, 575–577 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Perry, V. H. & Holmes, C. Microglial priming in neurodegenerative disease. Nature Rev. Neurol. 10, 217–224 (2014).
  Article CAS Google Scholar
• Cunningham, C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71–90 (2013).
  Article PubMed Google Scholar
• Sudduth, T. L., Schmitt, F. A., Nelson, P. T. & Wilcock, D. M. Neuroinflammatory phenotype in early Alzheimer's disease. Neurobiol. Aging 34, 1051–1059 (2013).
  Article CAS PubMed Google Scholar
• Krstic, D. & Knuesel, I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nature Rev. Neurol. 9, 25–34 (2013).
  Article CAS Google Scholar
• Hickman, S. E. & El Khoury, J. TREM2 and the neuroimmunology of Alzheimer's disease. Biochem. Pharmacol. 88, 495–498 (2014).
  Article CAS PubMed Google Scholar
• Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nature Rev. Immunol. 14, 463–477 (2014).
  Article CAS Google Scholar
• Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).
  Article CAS PubMed Google Scholar
• Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2, 864–870 (1996). This report showed that all common forms of familial AD could be integrated into a unified pathogenic scheme.
  Article CAS PubMed Google Scholar
• LaFerla, F. M. & Green, K. N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006320 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Haass, C., Kaether, C., Thinakaran, G. & Sisodia, S. Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2, a006270 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Holmes, C. et al. Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216–223 (2008).
  Article CAS PubMed Google Scholar
• Giacobini, E. & Gold, G. Alzheimer disease therapy — moving from amyloid-β to tau. Nature Rev. Neurol. 9, 677–686 (2013).
  Article CAS Google Scholar
• Wyss-Coray, T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nature Med. 12, 1005–1015 (2006).
  CAS PubMed Google Scholar
• Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013). This tour-de-force of bioinformatics illuminated the heretofore cryptic relevance of inflammation-system genes for AD pathogenesis.
  Article CAS PubMed PubMed Central Google Scholar
• Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).
  Article CAS PubMed Google Scholar
• Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013). These two back-to-back studies identified rare variants of a single myeloid cell receptor as conferring surprisingly high risk for late-onset sporadic AD.
  Article CAS PubMed Google Scholar
• Bradshaw, E. M. et al. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nature Neurosci. 16, 848–850 (2013).
  Article CAS PubMed Google Scholar
• Tarkowski, E., Andreasen, N., Tarkowski, A. & Blennow, K. Intrathecal inflammation precedes development of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 74, 1200–1205 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Brosseron, F., Krauthausen, M., Kummer, M. & Heneka, M. T. Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: a comparative overview. Mol. Neurobiol. 50, 534–544 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Krstic, D. et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflamm. 9, 151 (2012). This study shows that unspecific immune activation maternally and postnatally in wild-type mice can induce full-blown AD pathology, thus causally linking (early) immune stimulation and the development of AD pathology.
  Article CAS Google Scholar
• Perry, V. H. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol. 120, 277–286 (2010).
  Article CAS PubMed Google Scholar
• Cunningham, C. et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol. Psychiatry 65, 304–312 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768–774 (2009). This mechanistic clinical research study showed that AD patients with frequent, mild intercurrent infections deteriorated more rapidly, supporting the influence of systemic inflammation on disease course.
  Article CAS PubMed PubMed Central Google Scholar
• Cribbs, D. H. et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J. Neuroinflamm. 9, 179 (2012).
  Article CAS Google Scholar
• Schwartz, M. & Shechter, R. Systemic inflammatory cells fight off neurodegenerative disease. Nature Rev. Neurol. 6, 405–410 (2010).
  Article CAS Google Scholar
• Kyrkanides, S. et al. Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice. J. Neuroinflamm. 8, 112 (2011).
  Article Google Scholar
• Abuabara, K. et al. Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K. Br. J. Dermatol. 163, 586–592 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gisondi, P. et al. Mild cognitive impairment in patients with moderate to severe chronic plaque psoriasis. Dermatology 228, 78–85 (2014).
  Article PubMed Google Scholar
• Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).
  Article CAS PubMed Google Scholar
• Takeda, S. et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes. Proc. Natl Acad. Sci. USA 107, 7036–7041 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Mayeux, R. et al. Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives. Ann. Neurol. 33, 494–501 (1993).
  Article CAS PubMed Google Scholar
• Heneka, M. T. et al. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J. Neurosci. 26, 1343–1354 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Rubartelli, A. & Lotze, M. T. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 28, 429–436 (2007).
  Article CAS PubMed Google Scholar
• Bornemann, K. D. et al. Aβ-induced inflammatory processes in microglia cells of APP23 transgenic mice. Am. J. Pathol. 158, 63–73 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Stalder, A. K. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25, 11125–11132 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Eikelenboom, P. et al. Neuroinflammation in Alzheimer's disease and prion disease. Glia 40, 232–239 (2002).
  Article CAS PubMed Google Scholar
• Streit, W. J. Microglia and Alzheimer's disease pathogenesis. J. Neurosci. Res. 77, 1–8 (2004).
  Article CAS PubMed Google Scholar
• Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nature Neurosci. 14, 1227–1235 (2011).
  Article CAS PubMed Google Scholar
• International Multiple Sclerosis Genetics Consortium et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).
• Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genet. 43, 436–441 (2011).
  Article CAS PubMed Google Scholar
• Thambisetty, M. et al. Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. Biol. Psychiatry 73, 422–428 (2013).
  Article CAS PubMed Google Scholar
• Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094–1099 (2009).
  Article CAS PubMed Google Scholar
• Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet. 43, 429–435 (2011).
  Article CAS PubMed Google Scholar
• Liang, Y. & Tedder, T. F. Identification of a CD20-, FcɛRIβ-, and HTm4-related gene family: sixteen new MS4A family members expressed in human and mouse. Genomics 72, 119–127 (2001).
  Article CAS PubMed Google Scholar
• Ransohoff, R. M. Animal models of multiple sclerosis: the good, the bad and the bottom line. Nature Neurosci. 15, 1074–1077 (2012).
  Article CAS PubMed Google Scholar
• Raj, T. et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344, 519–523 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Iwashyna, T. J., Ely, E. W., Smith, D. M. & Langa, K. M. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304, 1787–1794 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nature Rev. Neurosci. 15, 300–312 (2014).
  Article CAS Google Scholar
• Du Yan, S. et al. Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc. Natl Acad. Sci. USA 94, 5296–5301 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• El Khoury, J. et al. Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 382, 716–719 (1996).
  Article CAS PubMed Google Scholar
• Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J. & Landreth, G. E. A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J. Neurosci. 23, 2665–2674 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Paresce, D. M., Ghosh, R. N. & Maxfield, F. R. Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 17, 553–565 (1996).
  Article CAS PubMed Google Scholar
• Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunol. 11, 155–161 (2010).
  Article CAS Google Scholar
• Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nature Immunol. 14, 812–820 (2013).
  Article CAS Google Scholar
• Koenigsknecht, J. & Landreth, G. Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism. J. Neurosci. 24, 9838–9846 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Fassbender, K. et al. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J. 18, 203–205 (2004).
  Article CAS PubMed Google Scholar
• El Khoury, J. B. et al. CD36 mediates the innate host response to β-amyloid. J. Exp. Med. 197, 1657–1666 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Griffin, W. S. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989).
  Article CAS PubMed PubMed Central Google Scholar
• Patel, N. S. et al. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. J. Neuroinflamm. 2, 9 (2005).
  Article CAS Google Scholar
• Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nature Med. 18, 1812–1819 (2012). This study showed that genetic as well as pharmacological blocking of the IL-12–IL-23 pathway substantially ameliorated AD pathology in an AD mouse model and provided the first hints that IL-12 and IL-23 are upregulted in the CSF of patients with AD, thus offering a druggable immune target made for repurposing existing IL-12 and IL-23 inhibitors.
  Article CAS PubMed Google Scholar
• Fillit, H. et al. Elevated circulating tumor necrosis factor levels in Alzheimer's disease. Neurosci. Lett. 129, 318–320 (1991).
  Article CAS PubMed Google Scholar
• Tan, J. et al. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nature Neurosci. 5, 1288–1293 (2002).
  Article CAS PubMed Google Scholar
• Tan, J. et al. Microglial activation resulting from CD40–CD40L interaction after β-amyloid stimulation. Science 286, 2352–2355 (1999).
  Article CAS PubMed Google Scholar
• Jin, J. J., Kim, H. D., Maxwell, J. A., Li, L. & Fukuchi, K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J. Neuroinflamm. 5, 23 (2008).
  Article CAS Google Scholar
• Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).
  Article CAS Google Scholar
• Lee, C. Y. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949–960 (2010).
  Article CAS PubMed Google Scholar
• Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004).
  Article PubMed Google Scholar
• Perry, V. H., Nicoll, J. A. & Holmes, C. Microglia in neurodegenerative disease. Nature Rev. Neurol. 6, 193–201 (2010).
  Article Google Scholar
• Krabbe, G. et al. Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS ONE 8, e60921 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Hickman, S. E., Allison, E. K. & El Khoury, J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354–8360 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lucin, K. M. et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron 79, 873–886 (2013). This paper shows that beclin 1 is altered in microglia derived from AD patients and provides the first molecular explanations of some aspects of microglial impairment in AD.
  Article CAS PubMed PubMed Central Google Scholar
• Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 330, 1774 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Grathwohl, S. A. et al. Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia. Nature Neurosci. 12, 1361–1363 (2009).
  Article CAS PubMed Google Scholar
• Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013). This paper demonstrates that microglia have an important role in learning and memory by providing neurotrophic factors, such as BDNF.
  Article CAS PubMed PubMed Central Google Scholar
• Hong, S. et al. Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82, 308–319 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Selkoe, D. J. SnapShot: pathobiology of Alzheimer's disease. Cell 154, 468–468 e1 (2013).
  Article CAS PubMed Google Scholar
• Verdier, Y., Zarandi, M. & Penke, B. Amyloid β–peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. J. Pept. Sci. 10, 229–248 (2004).
  Article CAS PubMed Google Scholar
• Wake, H., Moorhouse, A. J. & Nabekura, J. Functions of microglia in the central nervous system — beyond the immune response. Neuron Glia Biol. 7, 47–53 (2011).
  Article PubMed Google Scholar
• Salter, M. W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014).
  Article CAS PubMed Google Scholar
• Frank, S. et al. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56, 1438–1447 (2008).
  Article PubMed Google Scholar
• Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nature Neurosci. 16, 1896–1905 (2013).
  Article CAS PubMed Google Scholar
• Hsieh, C. L. et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J. Neurochem. 109, 1144–1156 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl Med. 6, 243ra86 (2014).
  Article PubMed CAS Google Scholar
• Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212, 287–295 (2015). These two publications show the importance and function of TREM2 in AD mouse models; that is, to promote the survival of activated microglia and myeloid cells, to recruit these cells to A β plaques through sensing for A β -associated lipids, and to modulate hippocampal A β burden.
  Article CAS PubMed PubMed Central Google Scholar
• Ulrich, J. D. et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Lajaunias, F., Dayer, J. M. & Chizzolini, C. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur. J. Immunol. 35, 243–251 (2005).
  Article CAS PubMed Google Scholar
• Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Miller, K. R. & Streit, W. J. The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol. 3, 245–253 (2007).
  Article PubMed Google Scholar
• El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Med. 13, 432–438 (2007).
  Article CAS PubMed Google Scholar
• Hawkes, C. A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 106, 1261–1266 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hickey, W. F. & Kimura, H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239, 290–292 (1988).
  Article CAS PubMed Google Scholar
• Lai, A. Y. & McLaurin, J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 7, 165–176 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159–11171 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Gomez-Nicola, D., Schetters, S. T. & Perry, V. H. Differential role of CCR2 in the dynamics of microglia and perivascular macrophages during prion disease. Glia 62, 1041–1052 (2014).
  Article PubMed PubMed Central Google Scholar
• Burda, J. E. & Sofroniew, M. V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229–248 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).
  Article PubMed Google Scholar
• Medeiros, R. & LaFerla, F. M. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp. Neurol. 239, 133–138 (2013).
  Article CAS PubMed Google Scholar
• Heneka, M. T. et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J. Neuroinflamm. 2, 22 (2005).
  Article CAS Google Scholar
• Olabarria, M., Noristani, H. N., Verkhratsky, A. & Rodriguez, J. J. Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer's disease mouse model: mechanism for deficient glutamatergic transmission? Mol. Neurodegener. 6, 55 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Olabarria, M., Noristani, H. N., Verkhratsky, A. & Rodriguez, J. J. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia 58, 831–838 (2010).
  PubMed Google Scholar
• Furman, J. L. et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer's disease. J. Neurosci. 32, 16129–16140 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Nagele, R. G., D'Andrea, M. R., Lee, H., Venkataraman, V. & Wang, H. Y. Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 971, 197–209 (2003).
  Article CAS PubMed Google Scholar
• Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nature Med. 9, 453–457 (2003). This paper demonstrates that astrocytes can have an important impact on catabolising A β.
  Article CAS PubMed Google Scholar
• Koistinaho, M. et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nature Med. 10, 719–726 (2004).
  Article CAS PubMed Google Scholar
• Terwel, D. et al. Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis. J. Neurosci. 31, 7049–7059 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Pihlaja, R. et al. Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes. Glia 59, 1643–1657 (2011).
  Article PubMed Google Scholar
• Saido, T. & Leissring, M. A. Proteolytic degradation of amyloid β-protein. Cold Spring Harb. Perspect. Med. 2, a006379 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• 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, a006346 (2012).
  Article PubMed PubMed Central Google Scholar
• Roth, A. D., Ramirez, G., Alarcon, R. & Von Bernhardi, R. Oligodendrocytes damage in Alzheimer's disease: beta amyloid toxicity and inflammation. Biol. Res. 38, 381–387 (2005).
  Article CAS PubMed Google Scholar
• Mitew, S. et al. Focal demyelination in Alzheimer's disease and transgenic mouse models. Acta Neuropathol. 119, 567–577 (2010).
  Article CAS PubMed Google Scholar
• Hosokawa, M., Klegeris, A., Maguire, J. & McGeer, P. L. Expression of complement messenger RNAs and proteins by human oligodendroglial cells. Glia 42, 417–423 (2003).
  Article PubMed Google Scholar
• Yamada, T., Akiyama, H. & McGeer, P. L. Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement proteins C3d and C4d. Neurosci. Lett. 112, 161–166 (1990).
  Article CAS PubMed Google Scholar
• Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl Acad. Sci. USA 95, 10896–10901 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, S. et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am. J. Pathol. 177, 2549–2562 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Singhrao, S. K., Muller, C. T., Gilbert, S. J., Duance, V. C. & Archer, C. W. An immunofluorescence method for postembedded tissue in the acrylic resin Technovit 9100 New using fluorescein isothiocyanate secondary detection. Microsc. Res. Tech. 72, 501–506 (2009).
  Article CAS PubMed Google Scholar
• Yang, L. B., Li, R., Meri, S., Rogers, J. & Shen, Y. Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer's disease. J. Neurosci. 20, 7505–7509 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Walker, D. G., Dalsing-Hernandez, J. E., Campbell, N. A. & Lue, L. F. Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation. Exp. Neurol. 215, 5–19 (2009).
  Article CAS PubMed Google Scholar
• Sagare, A. P., Bell, R. D. & Zlokovic, B. V. Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a011452 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Vukic, V. et al. Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK–AP1 signaling pathway. Neurobiol. Dis. 34, 95–106 (2009).
  Article CAS PubMed Google Scholar
• Palmer, J. C., Barker, R., Kehoe, P. G. & Love, S. Endothelin-1 is elevated in Alzheimer's disease and upregulated by amyloid-β. J. Alzheimers Dis. 29, 853–861 (2012).
  Article CAS PubMed Google Scholar
• Grammas, P. Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J. Neuroinflamm. 8, 26 (2011).
  Article CAS Google Scholar
• Lyros, E., Bakogiannis, C., Liu, Y. & Fassbender, K. Molecular links between endothelial dysfunction and neurodegeneration in Alzheimer's disease. Curr. Alzheimer Res. 11, 18–26 (2014).
  Article CAS PubMed Google Scholar
• Chiang, K. & Koo, E. H. Emerging therapeutics for Alzheimer's disease. Annu. Rev. Pharmacol. Toxicol. 54, 381–405 (2014).
  Article CAS PubMed Google Scholar
• Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E. & Heuschling, P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-β. J. Neuroimmunol. 210, 3–12 (2009).
  Article CAS PubMed Google Scholar
• Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).
  Article PubMed PubMed Central Google Scholar
• Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Anand, P., Singh, B., Jaggi, A. S. & Singh, N. Mast cells: an expanding pathophysiological role from allergy to other disorders. Naunyn Schmiedebergs Arch. Pharmacol. 385, 657–670 (2012).
  Article CAS PubMed Google Scholar
• Piette, F. et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res. Ther. 3, 16 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Breitner, J. C. & Zandi, P. P. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer's disease? N. Engl. J. Med. 345, 1567–1568 (2001).
  Article CAS PubMed Google Scholar
• in t' Veld, B. A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345, 1515–1521 (2001).
  Article CAS PubMed Google Scholar
• Aisen, P. S. The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease. Lancet Neurol. 1, 279–284 (2002).
  Article CAS PubMed Google Scholar
• Group, A. R. et al. Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch. Neurol. 65, 896–905 (2008).
  Article Google Scholar
• Group, A. R. et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 68, 1800–1808 (2007).
  Article CAS Google Scholar
• Aisen, P. S. et al. Effects of rofecoxib or naproxen versus placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 2819–2826 (2003).
  Article CAS PubMed Google Scholar
• Breitner, J. C. et al. Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 7, 402–411 (2011).
  Article PubMed PubMed Central Google Scholar
• Lo, A. W., Ho, C., Cummings, J. & Kosik, K. S. Parallel discovery of Alzheimer's therapeutics. Sci. Transl Med. 6, 241cm5 (2014).
  Article PubMed Google Scholar
• Guerreiro, R. J. et al. Peripheral inflammatory cytokines as biomarkers in Alzheimer's disease and mild cognitive impairment. Neurodegener. Dis. 4, 406–412 (2007).
  Article CAS PubMed Google Scholar
• Hu, W. T. et al. Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology 79, 897–905 (2012). Using an unbiased proteome approach, this study provides evidence for changes in immune-relevant factors in the plasma of MCI and AD patients.
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y. et al. Interleukin-23 receptor polymorphisms are associated with Alzheimer's disease in Han Chinese. J. Neuroimmunol. 271, 43–48 (2014).
  Article CAS PubMed Google Scholar
• Tan, M. S. et al. IL12/23 p40 inhibition ameliorates Alzheimer's disease-associated neuropathology and spatial memory in SAMP8 mice. J. Alzheimers Dis. 38, 633–646 (2014).
  Article CAS PubMed Google Scholar
• Griffin, W. S. Neuroinflammatory cytokine signaling and Alzheimer's disease. N. Engl. J. Med. 368, 770–771 (2013).
  Article CAS PubMed Google Scholar
• Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008).
  Article CAS Google Scholar
• Heneka, M. T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013). This study shows that NLRP3 activation occurs in microglia in patients with AD and provides evidence that inhibition of NLRP3 reduces AD pathology in vivo.
  Article CAS PubMed Google Scholar
• Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Med. 21, 248–255 (2015).
  Article CAS PubMed Google Scholar
• Yamanaka, M. et al. PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J. Neurosci. 32, 17321–17331 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Veeraraghavalu, K. et al. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 340, 924-f (2013).
  Article PubMed CAS Google Scholar
• Tesseur, I. et al. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 340, 924-e (2013).
  Article PubMed CAS Google Scholar
• Price, A. R. et al. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 340, 924-d (2013).
  Article PubMed CAS Google Scholar
• Fitz, N. F., Cronican, A. A., Lefterov, I. & Koldamova, R. Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. Science 340, 924-c (2013).
  Article PubMed CAS Google Scholar
• Fuhrmann, M. et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nature Neurosci. 13, 411–413 (2010).
  Article CAS PubMed Google Scholar
• Nash, K. R. et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol. Aging 34, 1540–1548 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Frenkel, D. et al. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nature Commun. 4, 2030 (2013).
  Article CAS Google Scholar
• Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl Acad. Sci. USA 99, 10837–10842 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Fonseca, M. I., Zhou, J., Botto, M. & Tenner, A. J. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J. Neurosci. 24, 6457–6465 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Maier, M. et al. Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J. Neurosci. 28, 6333–6341 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).
  Article CAS PubMed Google Scholar
• Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).
  Article CAS PubMed Google Scholar
• van der Wal, E. A., Gómez-Pinilla, F. & Cotman, C. W. Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport 4, 69–72 (1993).
  Article CAS PubMed Google Scholar
• Wyss-Coray, T. et al. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nature Med. 7, 612–618 (2001).
  Article CAS PubMed Google Scholar
• Town, T. et al. Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nature Med. 14, 681–687 (2008). This paper demonstrates that inhibition of TGF β in myeloid cells can reduce AD pathology in mice.
  Article CAS PubMed Google Scholar
• Swardfager, W. et al. A meta-analysis of cytokines in Alzheimer's disease. Biol. Psychiatry 68, 930–941 (2010).
  Article CAS PubMed Google Scholar
• Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489–502 (2006).
  Article CAS PubMed Google Scholar
• Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease. Nature Med. 6, 916–919 (2000).
  Article CAS PubMed Google Scholar
• Garcia-Alloza, M. et al. A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol. Dis. 28, 286–292 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Golde, T. E., Das, P. & Levites, Y. Quantitative and mechanistic studies of Aβ immunotherapy. CNS Neurol. Disord. Drug Targets 8, 31–49 (2009).
  Article CAS PubMed Google Scholar
• Koenigsknecht-Talboo, J. et al. Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J. Neurosci. 28, 14156–14164 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wilcock, D. M. et al. Intracranially administered anti-Aβ antibodies reduce β-amyloid deposition by mechanisms both independent of and associated with microglial activation. J. Neurosci. 23, 3745–3751 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Wilcock, D. M. et al. Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol. Dis. 15, 11–20 (2004).
  Article CAS PubMed Google Scholar
• Wilcock, D. M. et al. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J. Neurosci. 24, 6144–6151 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, A., Das, P., Switzer, R. C. 3rd, Golde, T. E. & Jankowsky, J. L. Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-β immunotherapy. J. Neurosci. 31, 4124–4136 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Citron, M. Alzheimer's disease: strategies for disease modification. Nature Rev. Drug Discov. 9, 387–398 (2010).
  Article CAS Google Scholar
• Medeiros, R. et al. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice. Am. J. Pathol. 182, 1780–1789 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Kiyota, T. et al. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Gene Ther. 19, 724–733 (2012).
  Article CAS PubMed Google Scholar
• Chakrabarty, P. et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519–533 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Jin, P. et al. Anti-inflammatory and anti-amyloidogenic effects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer's disease mice model. J. Neuroinflamm. 10, 2 (2013).
  CAS Google Scholar
• Chakrabarty, P. et al. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol. Neurodegener. 7, 36 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Imbimbo, B. P. et al. CHF5074, a novel γ-secretase modulator, attenuates brain β-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease. Br. J. Pharmacol. 156, 982–993 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Sivilia, S. et al. Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice. BMC Neurosci. 14, 44 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• CERESPIR. CERESPIR Incorporated is pleased with positive interim Phase 2 results for CHF 5074 in patients with mild cognitive impairment, presented by Chiesi at the AAIC 2013 Meeting in Boston. CERESPIR [online], (2013).
• Ross, J. et al. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr. Alzheimer Res. 10, 742–753 (2013).
  Article CAS PubMed Google Scholar
• Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Med. 20, 659–663 (2014). These two studies show that changes in blood-borne factors including immune molecules such as the chemokine CCL11 are linked to impaired neurogenesis and decline in cognitive performance during ageing, which can be rescued by transfer of young blood to aged mice.
  Article CAS PubMed Google Scholar
• Mackaness, G. B. Cellular resistance to infection. J. Exp. Med. 116, 381–406 (1962).
  Article CAS PubMed PubMed Central Google Scholar
• Nathan, C. F., Murray, H. W., Wiebe, M. E. & Rubin, B. Y. Identification of interferon-γ as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158, 670–689 (1983).
  Article CAS PubMed Google Scholar
• Stein, M., Keshav, S., Harris, N. & Gordon, S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992).
  Article CAS PubMed Google Scholar
• Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).
  CAS PubMed Google Scholar
• Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).
  Article CAS PubMed Google Scholar
• Vahedi, G., Kanno, Y., Sartorelli, V. & O'Shea, J. J. Transcription factors and CD4 T cells seeking identity: masters, minions, setters and spikers. Immunology 139, 294–298 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Hirahara, K. et al. Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 134, 235–245 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Josefowicz, S. Z. Regulators of chromatin state and transcription in CD4 T-cell polarization. Immunology 139, 299–308 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nature Rev. Immunol. 11, 750–761 (2011).
  Article CAS Google Scholar
• Lacey, D. C. et al. Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. J. Immunol. 188, 5752–5765 (2012).
  Article CAS PubMed Google Scholar
• Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Mucke, L. & Selkoe, D. J. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb. Perspect. Med. 2, a006338 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Cui, Y. H. et al. Up-regulation of FPR2, a chemotactic receptor for amyloid β 1–42 (Aβ42), in murine microglial cells by TNFα. Neurobiol. Dis. 10, 366–377 (2002).
  Article CAS PubMed Google Scholar
• Lotz, M. et al. Amyloid beta peptide 1–40 enhances the action of Toll-like receptor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced inflammation in primary mouse microglial cell cultures. J. Neurochem. 94, 289–298 (2005).
  Article CAS PubMed Google Scholar
• Reed-Geaghan, E. G., Savage, J. C., Hise, A. G. & Landreth, G. E. CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J. Neurosci. 29, 11982–11992 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hu, J., Akama, K. T., Krafft, G. A., Chromy, B. A. & Van Eldik, L. J. Amyloid-β peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res. 785, 195–206 (1998).
  Article CAS PubMed Google Scholar
• Larson, M. et al. The complex PrPc–Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J. Neurosci. 32, 16857-71a (2012).
  PubMed Google Scholar
• Papassotiropoulos, A. et al. A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease. Ann. Neurol. 45, 666–668 (1999).
  Article CAS PubMed Google Scholar
• Chakrabarty, P. et al. Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 24, 548–559 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Chakrabarty, P., Herring, A., Ceballos-Diaz, C., Das, P. & Golde, T. E. Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo. Mol. Neurodegener. 6, 16 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Li, R. et al. Tumor necrosis factor death receptor signaling cascade is required for amyloid-β protein-induced neuron death. J. Neurosci. 24, 1760–1771 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, X., Yang, L., He, P., Li, R. & Shen, Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients. J. Alzheimers Dis. 19, 621–630 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tobinick, E. L. & Gross, H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J. Neuroinflamm. 5, 2 (2008).
  Article CAS Google Scholar
• Ryu, J. K. & McLarnon, J. G. Block of purinergic P2X7 receptor is neuroprotective in an animal model of Alzheimer's disease. Neuroreport 19, 1715–1719 (2008).
  Article CAS PubMed Google Scholar
• Diaz-Hernandez, J. I. et al. In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases. Neurobiol. Aging 33, 1816–1828 (2012).
  Article CAS PubMed Google Scholar