Review Special Issues

The role of immunity and neuroinflammation in genetic predisposition and pathogenesis of Alzheimer's disease

  • Received: 08 July 2015 Accepted: 22 September 2015 Published: 25 January 2015
  • Alzheimer's disease is an important public concern with rising prevalence across the globe. While many therapeutic approaches for Alzheimer's disease have been developed, there are currently no validated disease-modifying treatments. Thus, in order to develop novel treatment strategies, there is a significant need to progress our understanding of the pathogenesis of Alzheimer's disease. Several large genome-wide association studies and whole genome and exome sequencing studies have identified novel genes associated with late-onset Alzheimer's disease. Interestingly, many of the genes are associated with inflammation and the immune system, including complement receptor 1, clusterin, CD33, EPH receptor A1, membrane-spanning 4-domains subfamily A, ATP-binding cassette sub-family A member 7, major histocompatibility complex class II, inositol polyphosphate-5-phosphatase, myocyte enhancer factor 2C, and triggering receptor expressed on myeloid cells 2. The pathogenetic contributions of immune reaction and neuroinflammation in Alzheimer's disease have been regarded largely as part of amyloid cascade hypothesis. The neurotoxic amyloid-β (Aβ) induces activation of immune cells, such as microglia, astrocytes, perivascular macrophages and lymphocytes and decreased capability of clearing Aβ by immune system and chronic inflammation caused by activated immune cells aggravate neuronal damage and eventually Alzheimer's disease. But the precise mechanism and hereditary impact on such process is largely unknown. The current findings in genetic studies suggest that the immunological mechanisms of Alzheimer's disease may extend beyond passive reaction of Aβ, including the development of Alzheimer's disease such as time of onset and rate of progression. In this article, we aimed to review the mechanisms of immune reaction and neuroinflammation in Alzheimer's disease, with an emphasis on the function of genes known to be associated with a risk of Alzheimer's disease in terms of neuroinflammation and immune function.

    Citation: Seoyoung Yoon, Yong-Ku Kim. The role of immunity and neuroinflammation in genetic predisposition and pathogenesis of Alzheimer's disease[J]. AIMS Genetics, 2015, 2(3): 230-249. doi: 10.3934/genet.2015.3.230

    Related Papers:

  • Alzheimer's disease is an important public concern with rising prevalence across the globe. While many therapeutic approaches for Alzheimer's disease have been developed, there are currently no validated disease-modifying treatments. Thus, in order to develop novel treatment strategies, there is a significant need to progress our understanding of the pathogenesis of Alzheimer's disease. Several large genome-wide association studies and whole genome and exome sequencing studies have identified novel genes associated with late-onset Alzheimer's disease. Interestingly, many of the genes are associated with inflammation and the immune system, including complement receptor 1, clusterin, CD33, EPH receptor A1, membrane-spanning 4-domains subfamily A, ATP-binding cassette sub-family A member 7, major histocompatibility complex class II, inositol polyphosphate-5-phosphatase, myocyte enhancer factor 2C, and triggering receptor expressed on myeloid cells 2. The pathogenetic contributions of immune reaction and neuroinflammation in Alzheimer's disease have been regarded largely as part of amyloid cascade hypothesis. The neurotoxic amyloid-β (Aβ) induces activation of immune cells, such as microglia, astrocytes, perivascular macrophages and lymphocytes and decreased capability of clearing Aβ by immune system and chronic inflammation caused by activated immune cells aggravate neuronal damage and eventually Alzheimer's disease. But the precise mechanism and hereditary impact on such process is largely unknown. The current findings in genetic studies suggest that the immunological mechanisms of Alzheimer's disease may extend beyond passive reaction of Aβ, including the development of Alzheimer's disease such as time of onset and rate of progression. In this article, we aimed to review the mechanisms of immune reaction and neuroinflammation in Alzheimer's disease, with an emphasis on the function of genes known to be associated with a risk of Alzheimer's disease in terms of neuroinflammation and immune function.


    加载中
    [1] World Health Organization, The global burden of disease: 2004 update. Geneva 27, Switzerland, World Health Organization, 2008. Available from: http: //www.who.int/healthinfo/global_burden_disease/2004_report_update/en/
    [2] Ferri CP, Prince M, Brayne C, et al. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366: 2112-2117. doi: 10.1016/S0140-6736(05)67889-0
    [3] Prince M, Bryce R, Albanese E, et al. (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9: 63-75.e62. doi: 10.1016/j.jalz.2012.11.007
    [4] Brookmeyer R, Johnson E, Ziegler-Graham K, et al. (2007) Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 3: 186-191. doi: 10.1016/j.jalz.2007.04.381
    [5] Hardy JA, Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256: 184-185. doi: 10.1126/science.1566067
    [6] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356. doi: 10.1126/science.1072994
    [7] Povova J, Ambroz P, Bar M, et al. (2012) Epidemiological of and risk factors for Alzheimer's disease: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 156: 108-114. doi: 10.5507/bp.2012.055
    [8] Lautenschlager NT, Cupples LA, Rao VS, et al. (1996) Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old? Neurology 46: 641-650. doi: 10.1212/WNL.46.3.641
    [9] Raiha I, Kaprio J, Koskenvuo M, et al. (1996) Alzheimer's disease in Finnish twins. Lancet 347: 573-578. doi: 10.1016/S0140-6736(96)91272-6
    [10] Gatz M, Reynolds CA, Fratiglioni L, et al. (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63: 168-174. doi: 10.1001/archpsyc.63.2.168
    [11] Bergem AL, Engedal K, Kringlen E (1997) The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 54: 264-270.
    [12] Gatz M, Pedersen NL, Berg S, et al. (1997) Heritability for Alzheimer's disease: the study of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci 52: M117-125.
    [13] Coon KD, Myers AJ, Craig DW, et al. (2007) A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry 68: 613-618. doi: 10.4088/JCP.v68n0419
    [14] Couzin J (2008) Genetics. Once shunned, test for Alzheimer's risk headed to market. Science 319: 1022-1023.
    [15] Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2: a006312.
    [16] Farrer LA, Cupples LA, Haines JL, et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278: 1349-1356.
    [17] Kim KW, Jhoo JH, Lee KU, et al. (1999) Association between apolipoprotein E polymorphism and Alzheimer's disease in Koreans. Neurosci Lett 277: 145-148. doi: 10.1016/S0304-3940(99)00867-8
    [18] Lambert JC, Amouyel P (2011) Genetics of Alzheimer's disease: new evidences for an old hypothesis? Curr Opin Genet Dev 21: 295-301. doi: 10.1016/j.gde.2011.02.002
    [19] Bertram L, McQueen MB, Mullin K, et al. (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39: 17-23. doi: 10.1038/ng1934
    [20] Rogaeva E, Meng Y, Lee JH, et al. (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39: 168-177. doi: 10.1038/ng1943
    [21] Reitz C, Cheng R, Rogaeva E, et al. (2011) Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Arch Neurol 68: 99-106. doi: 10.1001/archneurol.2010.346
    [22] Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678. doi: 10.1038/nature05911
    [23] Chouraki V, Seshadri S (2014) Genetics of Alzheimer's disease. Adv Genet 87: 245-294. doi: 10.1016/B978-0-12-800149-3.00005-6
    [24] Jonsson T, Stefansson H, Steinberg S, et al. (2013) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368: 107-116. doi: 10.1056/NEJMoa1211103
    [25] Cruchaga C, Karch CM, Jin SC, et al. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505: 550-554.
    [26] Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119: 89-105. doi: 10.1007/s00401-009-0622-0
    [27] Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27: 119-145. doi: 10.1146/annurev.immunol.021908.132528
    [28] Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40: 133-139. doi: 10.1002/glia.10154
    [29] Dickson DW, Farlo J, Davies P, et al. (1988) Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol 132: 86-101.
    [30] Guillot-Sestier MV, Town T (2013) Innate immunity in Alzheimer's disease: a complex affair. CNS Neurol Disord Drug Targets 12: 593-607. doi: 10.2174/1871527311312050008
    [31] Coraci IS, Husemann J, Berman JW, et al. (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160: 101-112. doi: 10.1016/S0002-9440(10)64354-4
    [32] Bamberger ME, Harris ME, McDonald DR, et al. (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23: 2665-2674.
    [33] Frenkel D, Wilkinson K, Zhao L, et al. (2013) Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun 4: 2030.
    [34] Walter S, Letiembre M, Liu Y, et al. (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem 20: 947-956. doi: 10.1159/000110455
    [35] Scholtzova H, Chianchiano P, Pan J, et al. (2014) Amyloid beta and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun 2: 101.
    [36] Wang LZ, Tian Y, Yu JT, et al. (2011) Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene. Neurosci Lett 489: 164-167. doi: 10.1016/j.neulet.2010.12.008
    [37] Liu Y, Walter S, Stagi M, et al. (2005) LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain 128: 1778-1789. doi: 10.1093/brain/awh531
    [38] Prokop S, Miller KR, Heppner FL (2013) Microglia actions in Alzheimer's disease. Acta Neuropathol 126: 461-477. doi: 10.1007/s00401-013-1182-x
    [39] Lee CY, Landreth GE (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm 117: 949-960. doi: 10.1007/s00702-010-0433-4
    [40] Stewart CR, Stuart LM, Wilkinson K, et al. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11: 155-161. doi: 10.1038/ni.1836
    [41] Town T, Nikolic V, Tan J (2005) The microglial ""activation"" continuum: from innate to adaptive responses. J Neuroinflammation 2: 24. doi: 10.1186/1742-2094-2-24
    [42] Varnum MM, Ikezu T (2012) The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain. Arch Immunol Ther Exp (Warsz) 60: 251-266. doi: 10.1007/s00005-012-0181-2
    [43] Mantovani A, Sozzani S, Locati M, et al. (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549-555. doi: 10.1016/S1471-4906(02)02302-5
    [44] Goerdt S, Orfanos CE (1999) Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10: 137-142. doi: 10.1016/S1074-7613(00)80014-X
    [45] Jimenez S, Baglietto-Vargas D, Caballero C, et al. (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: 11650-11661. doi: 10.1523/JNEUROSCI.3024-08.2008
    [46] Hoozemans JJ, Veerhuis R, Rozemuller JM, et al. (2006) Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology. Int J Dev Neurosci 24: 157-165. doi: 10.1016/j.ijdevneu.2005.11.001
    [47] Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6: 13.
    [48] Simard AR, Soulet D, Gowing G, et al. (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49: 489-502. doi: 10.1016/j.neuron.2006.01.022
    [49] Mandrekar S, Jiang Q, Lee CY, et al. (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29: 4252-4262. doi: 10.1523/JNEUROSCI.5572-08.2009
    [50] Yuyama K, Sun H, Mitsutake S, et al. (2012) Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J Biol Chem 287: 10977-10989. doi: 10.1074/jbc.M111.324616
    [51] Maier M, Peng Y, Jiang L, et al. (2008) Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 28: 6333-6341. doi: 10.1523/JNEUROSCI.0829-08.2008
    [52] Webster S, Lue LF, Brachova L, et al. (1997) Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiol Aging 18: 415-421. doi: 10.1016/S0197-4580(97)00042-0
    [53] Flanary BE, Streit WJ (2004) Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45: 75-88. doi: 10.1002/glia.10301
    [54] Griffin WS, Sheng JG, Royston MC, et al. (1998) Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 8: 65-72.
    [55] Griffin WS, Stanley LC, Ling C, et al. (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86: 7611-7615. doi: 10.1073/pnas.86.19.7611
    [56] Barger SW, Harmon AD (1997) Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388: 878-881. doi: 10.1038/42257
    [57] Li Y, Liu L, Barger SW, et al. (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 23: 1605-1611.
    [58] Li Y, Liu L, Kang J, et al. (2000) Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci 20: 149-155.
    [59] Sheng JG, Ito K, Skinner RD, et al. (1996) In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiol Aging 17: 761-766. doi: 10.1016/0197-4580(96)00104-2
    [60] Yamanaka M, Ishikawa T, Griep A, et al. (2012) PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32: 17321-17331. doi: 10.1523/JNEUROSCI.1569-12.2012
    [61] Tarkowski E, Andreasen N, Tarkowski A, et al. (2003) Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry 74: 1200-1205. doi: 10.1136/jnnp.74.9.1200
    [62] Sheng JG, Jones RA, Zhou XQ, et al. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int 39: 341-348. doi: 10.1016/S0197-0186(01)00041-9
    [63] Munoz L, Ralay Ranaivo H, Roy SM, et al. (2007) A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model. J Neuroinflammation 4: 21. doi: 10.1186/1742-2094-4-21
    [64] Yoshiyama Y, Higuchi M, Zhang B, et al. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53: 337-351. doi: 10.1016/j.neuron.2007.01.010
    [65] Butterfield DA, Swomley AM, Sultana R (2013) Amyloid beta-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19: 823-835. doi: 10.1089/ars.2012.5027
    [66] Thiabaud G, Pizzocaro S, Garcia-Serres R, et al. (2013) Heme binding induces dimerization and nitration of truncated beta-amyloid peptide Abeta16 under oxidative stress. Angew Chem Int Ed Engl 52: 8041-8044. doi: 10.1002/anie.201302989
    [67] Nathan C, Calingasan N, Nezezon J, et al. (2005) Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase. J Exp Med 202: 1163-1169. doi: 10.1084/jem.20051529
    [68] Aboud O, Parcon PA, DeWall KM, et al. (2015) Aging, Alzheimer's, and APOE genotype influence the expression and neuronal distribution patterns of microtubule motor protein dynactin-P50. Front Cell Neurosci 9: 103.
    [69] Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 28: 8354-8360. doi: 10.1523/JNEUROSCI.0616-08.2008
    [70] Lai AY, McLaurin J (2012) Clearance of amyloid-beta peptides by microglia and macrophages: the issue of what, when and where. Future Neurol 7: 165-176. doi: 10.2217/fnl.12.6
    [71] Hawkes CA, McLaurin J (2009) Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci U S A 106: 1261-1266. doi: 10.1073/pnas.0805453106
    [72] Mildner A, Schlevogt B, Kierdorf K, et al. (2011) Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J Neurosci 31: 11159-11171. doi: 10.1523/JNEUROSCI.6209-10.2011
    [73] Stalder AK, Ermini F, Bondolfi L, et al. (2005) Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci 25: 11125-11132. doi: 10.1523/JNEUROSCI.2545-05.2005
    [74] Malm TM, Koistinaho M, Parepalo M, et al. (2005) Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 18: 134-142 doi: 10.1016/j.nbd.2004.09.009
    [75] Fiala M, Liu PT, Espinosa-Jeffrey A, et al. (2007) Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci U S A 104: 12849-12854. doi: 10.1073/pnas.0701267104
    [76] Mildner A, Schmidt H, Nitsche M, et al. (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10: 1544-1553. doi: 10.1038/nn2015
    [77] Ajami B, Bennett JL, Krieger C, et al. (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10: 1538-1543. doi: 10.1038/nn2014
    [78] Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16: 358-372. doi: 10.1038/nrn3880
    [79] Togo T, Akiyama H, Iseki E, et al. (2002) Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J Neuroimmunol 124: 83-92. doi: 10.1016/S0165-5728(01)00496-9
    [80] Town T, Tan J, Flavell RA, et al. (2005) T-cells in Alzheimer's disease. Neuromolecular Med 7: 255-264. doi: 10.1385/NMM:7:3:255
    [81] Hohsfield LA, Humpel C (2015) Migration of blood cells to beta-amyloid plaques in Alzheimer's disease. Exp Gerontol 65: 8-15. doi: 10.1016/j.exger.2015.03.002
    [82] Fisher Y, Nemirovsky A, Baron R, et al. (2011) Dendritic cells regulate amyloid-beta-specific T-cell entry into the brain: the role of perivascular amyloid-beta. J Alzheimers Dis 27: 99-111.
    [83] Zhang J, Ke KF, Liu Z, et al. (2013) Th17 cell-mediated neuroinflammation is involved in neurodegeneration of abeta1-42-induced Alzheimer's disease model rats. PLoS One 8: e75786. doi: 10.1371/journal.pone.0075786
    [84] Gonzalez H, Pacheco R (2014) T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J Neuroinflammation 11: 201. doi: 10.1186/s12974-014-0201-8
    [85] Browne TC, McQuillan K, McManus RM, et al. (2013) IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol 190: 2241-2251. doi: 10.4049/jimmunol.1200947
    [86] Fisher Y, Strominger I, Biton S, et al. (2014) Th1 polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance. J Immunol 192: 92-102. doi: 10.4049/jimmunol.1301707
    [87] Richartz-Salzburger E, Batra A, Stransky E, et al. (2007) Altered lymphocyte distribution in Alzheimer's disease. J Psychiatr Res 41: 174-178. doi: 10.1016/j.jpsychires.2006.01.010
    [88] Bonotis K, Krikki E, Holeva V, et al. (2008) Systemic immune aberrations in Alzheimer's disease patients. J Neuroimmunol 193: 183-187. doi: 10.1016/j.jneuroim.2007.10.020
    [89] Bulati M, Buffa S, Martorana A, et al. (2015) Double negative (IgG+IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer's disease patients and show a pro-inflammatory trafficking receptor phenotype. J Alzheimers Dis 44: 1241-1251.
    [90] Speciale L, Calabrese E, Saresella M, et al. (2007) Lymphocyte subset patterns and cytokine production in Alzheimer's disease patients. Neurobiol Aging 28: 1163-1169. doi: 10.1016/j.neurobiolaging.2006.05.020
    [91] Xiao M, Hu G (2014) Involvement of aquaporin 4 in astrocyte function and neuropsychiatric disorders. CNS Neurosci Ther 20: 385-390. doi: 10.1111/cns.12267
    [92] Grolla AA, Fakhfouri G, Balzaretti G, et al. (2013) Abeta leads to Ca(2)(+) signaling alterations and transcriptional changes in glial cells. Neurobiol Aging 34: 511-522. doi: 10.1016/j.neurobiolaging.2012.05.005
    [93] Kato S, Gondo T, Hoshii Y, et al. (1998) Confocal observation of senile plaques in Alzheimer's disease: senile plaque morphology and relationship between senile plaques and astrocytes. Pathol Int 48: 332-340. doi: 10.1111/j.1440-1827.1998.tb03915.x
    [94] Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, et al. (2012) Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer's disease. J Anat 221: 252-262. doi: 10.1111/j.1469-7580.2012.01536.x
    [95] Heneka MT, O'Banion MK, Terwel D, et al. (2010) Neuroinflammatory processes in Alzheimer's disease. J Neural Transm 117: 919-947. doi: 10.1007/s00702-010-0438-z
    [96] Avila-Munoz E, Arias C (2014) When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer's disease. Ageing Res Rev 18: 29-40. doi: 10.1016/j.arr.2014.07.004
    [97] Wyss-Coray T, Loike JD, Brionne TC, et al. (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9: 453-457. doi: 10.1038/nm838
    [98] Koistinaho M, Lin S, Wu X, et al. (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10: 719-726. doi: 10.1038/nm1058
    [99] Dezsi L, Tuka B, Martos D, et al. (2015) Alzheimer's disease, astrocytes and kynurenines. Curr Alzheimer Res 12: 462-480.
    [100] Chavez-Gutierrez L, Bammens L, Benilova I, et al. (2012) The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. Embo j 31: 2261-2274. doi: 10.1038/emboj.2012.79
    [101] Suh J, Choi SH, Romano DM, et al. (2013) ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80: 385-401. doi: 10.1016/j.neuron.2013.08.035
    [102] Jun G, Naj AC, Beecham GW, et al. (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67: 1473-1484. doi: 10.1001/archneurol.2010.201
    [103] Jin C, Liu X, Zhang F, et al. (2013) An updated meta-analysis of the association between SORL1 variants and the risk for sporadic Alzheimer's disease. J Alzheimers Dis 37: 429-437.
    [104] Li Y, Rowland C, Catanese J, et al. (2008) SORL1 variants and risk of late-onset Alzheimer's disease. Neurobiol Dis 29: 293-296. doi: 10.1016/j.nbd.2007.09.001
    [105] Xiao Q, Gil SC, Yan P, et al. (2012) Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem 287: 21279-21289. doi: 10.1074/jbc.M111.338376
    [106] Narayan P, Orte A, Clarke RW, et al. (2012) The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-beta(1-40) peptide. Nat Struct Mol Biol 19: 79-83.
    [107] Lambert JC, Heath S, Even G, et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41: 1094-1099. doi: 10.1038/ng.439
    [108] Terwel D, Steffensen KR, Verghese PB, et al. (2011) Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis. J Neurosci 31: 7049-7059. doi: 10.1523/JNEUROSCI.6546-10.2011
    [109] Jiang Q, Lee CY, Mandrekar S, et al. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58: 681-693. doi: 10.1016/j.neuron.2008.04.010
    [110] Maezawa I, Maeda N, Montine TJ, et al. (2006) Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice. J Neuroinflammation 3: 10. doi: 10.1186/1742-2094-3-10
    [111] Maezawa I, Nivison M, Montine KS, et al. (2006) Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J 20: 797-799
    [112] Zhao L, Lin S, Bales KR, et al. (2009) Macrophage-mediated degradation of beta-amyloid via an apolipoprotein E isoform-dependent mechanism. J Neurosci 29: 3603-3612. doi: 10.1523/JNEUROSCI.5302-08.2009
    [113] Seshadri S, Fitzpatrick AL, Ikram MA, et al. (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303: 1832-1840
    [114] Naj AC, Jun G, Beecham GW, et al. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet 43: 436-441. doi: 10.1038/ng.801
    [115] Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45: 1452-1458. doi: 10.1038/ng.2802
    [116] Reitz C (2014) Genetic loci associated with Alzheimer's disease. Future Neurol 9: 119-122 doi: 10.2217/fnl.14.1
    [117] Malik M, Simpson JF, Parikh I, et al. (2013) CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing. J Neurosci 33: 13320-13325. doi: 10.1523/JNEUROSCI.1224-13.2013
    [118] Hollingworth P, Harold D, Sims R, et al. (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43: 429-435. doi: 10.1038/ng.803
    [119] Jiang T, Yu JT, Hu N, et al. (2014) CD33 in Alzheimer's disease. Mol Neurobiol 49: 529-535. doi: 10.1007/s12035-013-8536-1
    [120] Bradshaw EM, Chibnik LB, Keenan BT, et al. (2013) CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16: 848-850. doi: 10.1038/nn.3435
    [121] Rohn TT (2013) The triggering receptor expressed on myeloid cells 2: ""TREM-ming"" the inflammatory component associated with Alzheimer's disease. Oxid Med Cell Longev 2013: 860959.
    [122] Le Ber I, De Septenville A, Guerreiro R, et al. (2014) Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiol Aging 35: 2419.e2423-2415.
    [123] Sasaki A, Kakita A, Yoshida K, et al. (2015) Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease. Neurogenetics. In press.
    [124] Lu Y, Liu W, Wang X (2015) TREM2 variants and risk of Alzheimer's disease: a meta-analysis. Neurol Sci. In press.
    [125] Ruiz A, Dols-Icardo O, Bullido MJ, et al. (2014) Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia. Neurobiol Aging 35: 444.e441-444.
    [126] Rajagopalan P, Hibar DP, Thompson PM (2013) TREM2 and neurodegenerative disease. N Engl J Med 369: 1565-1567.
    [127] Strohmeyer R, Ramirez M, Cole GJ, et al. (2002) Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer's disease brain. J Neuroimmunol 131: 135-146. doi: 10.1016/S0165-5728(02)00272-2
    [128] Karch CM, Jeng AT, Nowotny P, et al. (2012) Expression of novel Alzheimer's disease risk genes in control and Alzheimer's disease brains. PLoS One 7: e50976. doi: 10.1371/journal.pone.0050976
    [129] Brouwers N, Van Cauwenberghe C, Engelborghs S, et al. (2012) Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry 17: 223-233. doi: 10.1038/mp.2011.24
    [130] Rogers J, Li R, Mastroeni D, et al. (2006) Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol Aging 27: 1733-1739. doi: 10.1016/j.neurobiolaging.2005.09.043
    [131] Lue LF, Brachova L, Civin WH, et al. (1996) Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 55: 1083-1088. doi: 10.1097/00005072-199655100-00008
    [132] Mahmoudi R, Kisserli A, Novella JL, et al. (2015) Alzheimer's disease is associated with low density of the long CR1 isoform. Neurobiol Aging 36: 1766.e1765-1712.
    [133] Harold D, Abraham R, Hollingworth P, et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41: 1088-1093. doi: 10.1038/ng.440
    [134] Thambisetty M, Simmons A, Velayudhan L, et al. (2010) Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry 67: 739-748. doi: 10.1001/archgenpsychiatry.2010.78
    [135] Jones SE, Jomary C (2002) Clusterin. Int J Biochem Cell Biol 34: 427-431. doi: 10.1016/S1357-2725(01)00155-8
    [136] Bell RD, Sagare AP, Friedman AE, et al. (2007) Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27: 909-918.
    [137] Jehle AW, Gardai SJ, Li S, et al. (2006) ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol 174: 547-556. doi: 10.1083/jcb.200601030
    [138] Tanaka N, Abe-Dohmae S, Iwamoto N, et al. (2011) HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7. Atherosclerosis 217: 407-414. doi: 10.1016/j.atherosclerosis.2011.06.031
    [139] Wildsmith KR, Holley M, Savage JC, et al. (2013) Evidence for impaired amyloid beta clearance in Alzheimer's disease. Alzheimers Res Ther 5: 33. doi: 10.1186/alzrt187
    [140] Chan SL, Kim WS, Kwok JB, et al. (2008) ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem 106: 793-804. doi: 10.1111/j.1471-4159.2008.05433.x
    [141] Kim WS, Li H, Ruberu K, et al. (2013) Deletion of Abca7 increases cerebral amyloid-beta accumulation in the J20 mouse model of Alzheimer's disease. J Neurosci 33: 4387-4394. doi: 10.1523/JNEUROSCI.4165-12.2013
    [142] Proitsi P, Lee SH, Lunnon K, et al. (2014) Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood. Neurobiol Aging 35: 279-290. doi: 10.1016/j.neurobiolaging.2013.08.002
    [143] Zuccolo J, Bau J, Childs SJ, et al. (2010) Phylogenetic analysis of the MS4A and TMEM176 gene families. PLoS One 5: e9369. doi: 10.1371/journal.pone.0009369
    [144] Cruse G, Beaven MA, Music SC, et al. (2015) The CD20 homologue MS4A4 directs trafficking of KIT toward clathrin-independent endocytosis pathways and thus regulates receptor signaling and recycling. Mol Biol Cell 26: 1711-1727. doi: 10.1091/mbc.E14-07-1221
    [145] Doyle KP, Quach LN, Sole M (2015) B-lymphocyte-mediated delayed cognitive impairment following stroke. J Neurosci 35: 2133-2145. doi: 10.1523/JNEUROSCI.4098-14.2015
    [146] Ma J, Yu JT, Tan L (2015) MS4A Cluster in Alzheimer's Disease. Mol Neurobiol 51: 1240-1248. doi: 10.1007/s12035-014-8800-z
    [147] Wang HF, Tan L, Hao XK, et al. (2015) Effect of EPHA1 genetic variation on cerebrospinal fluid and neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer's disease cohorts. J Alzheimers Dis 44: 115-123.
    [148] Gerlai R (2001) Eph receptors and neural plasticity. Nat Rev Neurosci 2: 205-209. doi: 10.1038/35058582
    [149] Gerlai R (2002) EphB and NMDA receptors: components of synaptic plasticity coming together. Trends Neurosci 25: 180-181.
    [150] Kullander K, Klein R (2002) Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 3: 475-486. doi: 10.1038/nrm856
    [151] Coulthard MG, Morgan M, Woodruff TM, et al. (2012) Eph/Ephrin signaling in injury and inflammation. Am J Pathol 181: 1493-1503. doi: 10.1016/j.ajpath.2012.06.043
    [152] Ieguchi K (2015) Eph as a target in inflammation. Endocr Metab Immune Disord Drug Targets 15: 119-128. doi: 10.2174/1871530315666150316121302
    [153] Sakamoto A, Sugamoto Y, Tokunaga Y, et al. (2011) Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. J Int Med Res 39: 522-527. doi: 10.1177/147323001103900220
    [154] Viernes DR, Choi LB, Kerr WG, et al. (2014) Discovery and development of small molecule SHIP phosphatase modulators. Med Res Rev 34: 795-824. doi: 10.1002/med.21305
    [155] Gold MJ, Hughes MR, Antignano F, et al. (2015) Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain-containing inositol 5-phosphatase (SHIP-1). J Allergy Clin Immunol. In press.
    [156] Nowakowska BA, Obersztyn E, Szymanska K, et al. (2010) Severe mental retardation, seizures, and hypotonia due to deletions of MEF2C. Am J Med Genet B Neuropsychiatr Genet 153b: 1042-1051.
    [157] Xu Z, Yoshida T, Wu L, et al. (2015) Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-kappaB and KLF2. J Cell Physiol 230: 1310-1320. doi: 10.1002/jcp.24870
    [158] Aisen PS, Luddy A, Durner M, et al. (1998) HLA-DR4 influences glial activity in Alzheimer's disease hippocampus. J Neurol Sci 161: 66-69.
    [159] Zota V, Nemirovsky A, Baron R, et al. (2009) HLA-DR alleles in amyloid beta-peptide autoimmunity: a highly immunogenic role for the DRB1*1501 allele. J Immunol 183: 3522-3530. doi: 10.4049/jimmunol.0900620
    [160] Mansouri L, Messalmani M, Klai S, et al. (2015) Association of HLA-DR/DQ polymorphism with Alzheimer's disease. Am J Med Sci 349: 334-337. doi: 10.1097/MAJ.0000000000000416
    [161] Kobrosly R, van Wijngaarden E (2010) Associations between immunologic, inflammatory, and oxidative stress markers with severity of depressive symptoms: an analysis of the 2005-2006 National Health and Nutrition Examination Survey. Neurotoxicology 31: 126-133. doi: 10.1016/j.neuro.2009.10.005
    [162] Na KS, Jung HY, Kim YK (2014) The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 48: 277-286. doi: 10.1016/j.pnpbp.2012.10.022
    [163] Heneka MT, Carson MJ, El Khoury J, et al. (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol 14: 388-405. doi: 10.1016/S1474-4422(15)70016-5
  • Reader Comments
  • © 2015 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(5985) PDF downloads(1393) Cited by(0)

Article outline

Other Articles By Authors

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog