Cellular and Molecular Neurobiology

, Volume 35, Issue 1, pp 71–83 | Cite as

Microglial Aβ Receptors in Alzheimer’s Disease

  • Yang YuEmail author
  • Richard D. Ye
Review Paper


Amyloid β (Aβ) plays a pivotal role in the progression of Alzheimer’s disease (AD) through its neurotoxic and inflammatory effects. On one hand, Aβ binds to microglia and activates them to produce inflammatory mediators. On the other hand, Aβ is cleared by microglia through receptor-mediated phagocytosis and degradation. This review focuses on microglial membrane receptors that bind Aβ and contribute to microglial activation and/or Aβ phagocytosis and clearance. These receptors can be categorized into several groups. The scavenger receptors (SRs) include scavenger receptor A-1 (SCARA-1), MARCO, scavenger receptor B-1 (SCARB-1), CD36 and the receptor for advanced glycation end product (RAGE). The G protein-coupled receptors (GPCRs) are formyl peptide receptor 2 (FPR2) and chemokine-like receptor 1 (CMKLR1). There are also toll-like receptors (TLRs) including TLR2, TLR4, and the co-receptor CD14. Functionally, SCARA-1 and CMKLR1 are involved in the uptake of Aβ, and RAGE is responsible for the activation of microglia and production of proinflammatory mediators following Aβ binding. CD36, CD36/CD47/α6β1-intergrin, CD14/TLR2/TLR4, and FPR2 display both functions. Additionally, MARCO and SCARB-1 also exhibit the ability to bind Aβ and may be involved in the progression of AD. Here, we focus on the expression and distribution of these receptors in microglia and their roles in microglia interaction with Aβ. Finally, we discuss the potential therapeutic value of these receptors in AD.


Alzheimer’s disease Amyloid β Microglial cells Scavenger receptors G protein-coupled receptors Toll-like receptors 



This work was supported by grants from National Natural Science Foundation of China (Grant 31270941 to R.D.Y. and Grant 81200843 to Y.Y.), from National Basic Research Program of China (973 Program, Grant 2012CB518001, to R.D.Y.), and from the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant 20120073110069, to R.D.Y. and Grant 20120073120091, to Y.Y.). The authors declare no competing financial interests.


  1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421PubMedCentralPubMedGoogle Scholar
  2. Alarcon R, Fuenzalida C, Santibanez M, von Bernhardi R (2005) Expression of scavenger receptors in glial cells. Comparing the adhesion of astrocytes and microglia from neonatal rats to surface-bound beta-amyloid. J Biol Chem 280(34):30406–30415. doi: 10.1074/jbc.M414686200 PubMedGoogle Scholar
  3. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan CN (2005) Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 201(5):713–722. doi: 10.1084/jem.20042031 PubMedCentralPubMedGoogle Scholar
  4. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN (2007) Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol 178(6):3912–3917PubMedGoogle Scholar
  5. Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ (2011) Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Abeta). J Neuroinflammation 8:79. doi: 10.1186/1742-2094-8-79 PubMedCentralPubMedGoogle Scholar
  6. Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23(7):2665–2674PubMedGoogle Scholar
  7. Banati RB, Gehrmann J, Schubert P, Kreutzberg GW (1993) Cytotoxicity of microglia. Glia 7(1):111–118. doi: 10.1002/glia.440070117 PubMedGoogle Scholar
  8. Bao Y, Qin L, Kim E, Bhosle S, Guo H, Febbraio M, Haskew-Layton RE, Ratan R, Cho S (2012) CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab 32(8):1567–1577. doi: 10.1038/jcbfm.2012.52 PubMedCentralPubMedGoogle Scholar
  9. Blennow K, Dubois B, Fagan AM, Lewczuk P, de Leon MJ, Hampel H (2014) Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement. doi: 10.1016/j.jalz.2014.02.004 PubMedCentralGoogle Scholar
  10. Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28(16):4283–4292. doi: 10.1523/JNEUROSCI.4814-07.2008 PubMedCentralPubMedGoogle Scholar
  11. Bornemann KD, Wiederhold KH, Pauli C, Ermini F, Stalder M, Schnell L, Sommer B, Jucker M, Staufenbiel M (2001) Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice. Am J Pathol 158(1):63–73PubMedCentralPubMedGoogle Scholar
  12. Brandenburg LO, Konrad M, Wruck CJ, Koch T, Lucius R, Pufe T (2010) Functional and physical interactions between formyl-peptide-receptors and scavenger receptor MARCO and their involvement in amyloid beta 1-42-induced signal transduction in glial cells. J Neurochem 113(3):749–760. doi: 10.1111/j.1471-4159.2010.06637.x PubMedGoogle Scholar
  13. Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A et al (1993) Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol 143(6):1699–1712PubMedCentralPubMedGoogle Scholar
  14. Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, Marambaud P (2012) Resveratrol mitigates lipopolysaccharide- and Abeta-mediated microglial inflammation by inhibiting the TLR4/NF-kappaB/STAT signaling cascade. J Neurochem 120(3):461–472. doi: 10.1111/j.1471-4159.2011.07594.x PubMedCentralPubMedGoogle Scholar
  15. Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: new concepts. Brain Res Rev 53(2):344–354. doi: 10.1016/j.brainresrev.2006.11.002 PubMedGoogle Scholar
  16. Chen K, Zhang L, Huang J, Gong W, Dunlop NM, Wang JM (2008) Cooperation between NOD2 and Toll-like receptor 2 ligands in the up-regulation of mouse mFPR2, a G-protein-coupled Abeta42 peptide receptor, in microglial cells. J Leukoc Biol 83(6):1467–1475. doi: 10.1189/jlb.0907607 PubMedGoogle Scholar
  17. Choi BR, Cho WH, Kim J, Lee HJ, Chung C, Jeon WK, Han JS (2014) Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer’s disease. Exp Mol Med 46:e75. doi: 10.1038/emm.2013.147 PubMedCentralPubMedGoogle Scholar
  18. Christie RH, Freeman M, Hyman BT (1996) Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer’s disease. Am J Pathol 148(2):399–403PubMedCentralPubMedGoogle Scholar
  19. Chung H, Brazil MI, Irizarry MC, Hyman BT, Maxfield FR (2001) Uptake of fibrillar beta-amyloid by microglia isolated from MSR-A (type I and type II) knockout mice. NeuroReport 12(6):1151–1154PubMedGoogle Scholar
  20. Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB (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(1):101–112PubMedCentralPubMedGoogle Scholar
  21. Crouch PJ, Harding SM, White AR, Camakaris J, Bush AI, Masters CL (2008) Mechanisms of A beta mediated neurodegeneration in Alzheimer’s disease. Int J Biochem Cell Biol 40(2):181–198. doi: 10.1016/j.biocel.2007.07.013 PubMedGoogle Scholar
  22. Cui Y, Le Y, Yazawa H, Gong W, Wang JM (2002a) Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer’s disease. J Leukoc Biol 72(4):628–635PubMedGoogle Scholar
  23. Cui YH, Le Y, Gong W, Proost P, Van Damme J, Murphy WJ, Wang JM (2002b) Bacterial lipopolysaccharide selectively up-regulates the function of the chemotactic peptide receptor formyl peptide receptor 2 in murine microglial cells. J Immunol 168(1):434–442PubMedGoogle Scholar
  24. Cui YH, Le Y, Zhang X, Gong W, Abe K, Sun R, Van Damme J, Proost P, Wang JM (2002c) Up-regulation of FPR2, a chemotactic receptor for amyloid beta 1-42 (A beta 42), in murine microglial cells by TNF alpha. Neurobiol Dis 10(3):366–377PubMedGoogle Scholar
  25. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 122(4):1377–1392. doi: 10.1172/JCI58642 PubMedCentralPubMedGoogle Scholar
  26. Decker Y, McBean G, Godson C (2009) Lipoxin A4 inhibits IL-1beta-induced IL-8 and ICAM-1 expression in 1321N1 human astrocytoma cells. Am J Physiol Cell Physiol 296(6):C1420–C1427. doi: 10.1152/ajpcell.00380.2008 PubMedGoogle Scholar
  27. El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382(6593):716–719. doi: 10.1038/382716a0 PubMedGoogle Scholar
  28. El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med 197(12):1657–1666. doi: 10.1084/jem.20021546 PubMedCentralPubMedGoogle Scholar
  29. Elomaa O, Kangas M, Sahlberg C, Tuukkanen J, Sormunen R, Liakka A, Thesleff I, Kraal G, Tryggvason K (1995) Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages. Cell 80(4):603–609PubMedGoogle Scholar
  30. Elshourbagy NA, Li X, Terrett J, Vanhorn S, Gross MS, Adamou JE, Anderson KM, Webb CL, Lysko PG (2000) Molecular characterization of a human scavenger receptor, human MARCO. Eur J Biochem 267(3):919–926PubMedGoogle Scholar
  31. Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Schmidt AM, Chen JX, Yan SS (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24(4):1043–1055. doi: 10.1096/fj.09-139634 PubMedCentralPubMedGoogle Scholar
  32. Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K (2004) The LPS receptor (CD14) links innate immunity with Alzheimer’s disease. FASEB J 18(1):203–205. doi: 10.1096/fj.03-0364fje PubMedGoogle Scholar
  33. Fiala M, Liu PT, Espinosa-Jeffrey A, Rosenthal MJ, Bernard G, Ringman JM, Sayre J, Zhang L, Zaghi J, Dejbakhsh S, Chiang B, Hui J, Mahanian M, Baghaee A, Hong P, Cashman J (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(31):12849–12854. doi: 10.1073/pnas.0701267104 PubMedCentralPubMedGoogle Scholar
  34. 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-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4:2030. doi: 10.1038/ncomms3030 PubMedCentralPubMedGoogle Scholar
  35. Gantz I, Konda Y, Yang YK, Miller DE, Dierick HA, Yamada T (1996) Molecular cloning of a novel receptor (CMKLR1) with homology to the chemotactic factor receptors. Cytogenet Cell Genet 74(4):286–290PubMedGoogle Scholar
  36. Granucci F, Petralia F, Urbano M, Citterio S, Di Tota F, Santambrogio L, Ricciardi-Castagnoli P (2003) The scavenger receptor MARCO mediates cytoskeleton rearrangements in dendritic cells and microglia. Blood 102(8):2940–2947. doi: 10.1182/blood-2002-12-3651 PubMedGoogle Scholar
  37. Grathwohl SA, Kalin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12(11):1361–1363. doi: 10.1038/nn.2432 PubMedGoogle Scholar
  38. Guillot-Sestier MV, Town T (2013) Innate immunity in Alzheimer’s disease: a complex affair. CNS Neurol Disord: Drug Targets 12(5):593–607Google Scholar
  39. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. doi: 10.1126/science.1072994 PubMedGoogle Scholar
  40. Hickman SE, El Khoury J (2010) Mechanisms of mononuclear phagocyte recruitment in Alzheimer’s disease. CNS Neurol Disord: Drug Targets 9(2):168–173Google Scholar
  41. 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(33):8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008 PubMedCentralPubMedGoogle Scholar
  42. Honda M, Akiyama H, Yamada Y, Kondo H, Kawabe Y, Takeya M, Takahashi K, Suzuki H, Doi T, Sakamoto A, Ookawara S, Mato M, Gough PJ, Greaves DR, Gordon S, Kodama T, Matsushita M (1998) Immunohistochemical evidence for a macrophage scavenger receptor in Mato cells and reactive microglia of ischemia and Alzheimer’s disease. Biochem Biophys Res Commun 245(3):734–740. doi: 10.1006/bbrc.1998.8120 PubMedGoogle Scholar
  43. Huang FL, Shiao YJ, Hou SJ, Yang CN, Chen YJ, Lin CH, Shie FS, Tsay HJ (2013) Cysteine-rich domain of scavenger receptor AI modulates the efficacy of surface targeting and mediates oligomeric Abeta internalization. J Biomed Sci 20:54. doi: 10.1186/1423-0127-20-54 PubMedCentralPubMedGoogle Scholar
  44. Hughes DA, Fraser IP, Gordon S (1995) Murine macrophage scavenger receptor: in vivo expression and function as receptor for macrophage adhesion in lymphoid and non-lymphoid organs. Eur J Immunol 25(2):466–473. doi: 10.1002/eji.1830250224 PubMedGoogle Scholar
  45. Husemann J, Silverstein SC (2001) Expression of scavenger receptor class B, type I, by astrocytes and vascular smooth muscle cells in normal adult mouse and human brain and in Alzheimer’s disease brain. Am J Pathol 158(3):825–832. doi: 10.1016/S0002-9440(10)64030-8 PubMedCentralPubMedGoogle Scholar
  46. Husemann J, Loike JD, Kodama T, Silverstein SC (2001) Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar beta-amyloid. J Neuroimmunol 114(1–2):142–150PubMedGoogle Scholar
  47. Iribarren P, Chen K, Hu J, Zhang X, Gong W, Wang JM (2005) IL-4 inhibits the expression of mouse formyl peptide receptor 2, a receptor for amyloid beta1-42, TNF-alpha-activated microglia. J Immunol 175(9):6100–6106PubMedGoogle Scholar
  48. Iribarren P, Chen K, Gong W, Cho EH, Lockett S, Uranchimeg B, Wang JM (2007) Interleukin 10 and TNFalpha synergistically enhance the expression of the G protein-coupled formylpeptide receptor 2 in microglia. Neurobiol Dis 27(1):90–98. doi: 10.1016/j.nbd.2007.04.010 PubMedCentralPubMedGoogle Scholar
  49. Jana M, Palencia CA, Pahan K (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer’s disease. J Immunol 181(10):7254–7262PubMedCentralPubMedGoogle Scholar
  50. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 5:23. doi: 10.1186/1742-2094-5-23 PubMedCentralPubMedGoogle Scholar
  51. Jones RS, Minogue AM, Connor TJ, Lynch MA (2013) Amyloid-beta-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. J Neuroimmune Pharmacol 8(1):301–311. doi: 10.1007/s11481-012-9427-3 PubMedGoogle Scholar
  52. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. doi: 10.1038/nrd3505 PubMedGoogle Scholar
  53. Kawahara K, Suenobu M, Yoshida A, Koga K, Hyodo A, Ohtsuka H, Kuniyasu A, Tamamaki N, Sugimoto Y, Nakayama H (2012) Intracerebral microinjection of interleukin-4/interleukin-13 reduces beta-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice. Neuroscience 207:243–260. doi: 10.1016/j.neuroscience.2012.01.049 PubMedGoogle Scholar
  54. Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83(5):711–730. doi: 10.1002/jnr.20767 PubMedCentralPubMedGoogle Scholar
  55. Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341(6152):1399–1404. doi: 10.1126/science.1242077 PubMedGoogle Scholar
  56. Koenigsknecht J, Landreth G (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 24(44):9838–9846. doi: 10.1523/JNEUROSCI.2557-04.2004 PubMedGoogle Scholar
  57. Koenigsknecht-Talboo J, Landreth GE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 25(36):8240–8249. doi: 10.1523/JNEUROSCI.1808-05.2005 PubMedGoogle Scholar
  58. Kouadir M, Yang L, Tu J, Yin X, Zhou X, Zhao D (2011) Comparison of mRNA expression patterns of class B scavenger receptors in BV2 microglia upon exposure to amyloidogenic fragments of beta-amyloid and prion proteins. DNA Cell Biol 30(11):893–897. doi: 10.1089/dna.2011.1234 PubMedGoogle Scholar
  59. Krieger M (1997) The other side of scavenger receptors: pattern recognition for host defense. Curr Opin Lipidol 8(5):275–280PubMedGoogle Scholar
  60. Landreth GE, Reed-Geaghan EG (2009) Toll-like receptors in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153. doi: 10.1007/978-3-642-00549-7_8 PubMedCentralPubMedGoogle Scholar
  61. Le Y, Gong W, Tiffany HL, Tumanov A, Nedospasov S, Shen W, Dunlop NM, Gao JL, Murphy PM, Oppenheim JJ, Wang JM (2001) Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J Neurosci 21(2):RC123PubMedGoogle Scholar
  62. Lee HN, Surh YJ (2013) Resolvin D1-mediated NOX2 inactivation rescues macrophages undertaking efferocytosis from oxidative stress-induced apoptosis. Biochem Pharmacol 86(6):759–769. doi: 10.1016/j.bcp.2013.07.002 PubMedGoogle Scholar
  63. Lee YJ, Han SB, Nam SY, Oh KW, Hong JT (2010) Inflammation and Alzheimer’s disease. Arch Pharm Res 33(10):1539–1556. doi: 10.1007/s12272-010-1006-7 PubMedGoogle Scholar
  64. Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30(5):759–768. doi: 10.1016/j.neurobiolaging.2007.08.018 PubMedGoogle Scholar
  65. Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, Heine H, Penke B, Neumann H, Fassbender K (2005) LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 128(Pt 8):1778–1789. doi: 10.1093/brain/awh531 PubMedGoogle Scholar
  66. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rube CE, Walter J, Heneka MT, Hartmann T, Menger MD, Fassbender K (2012) TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 188(3):1098–1107. doi: 10.4049/jimmunol.1101121 PubMedGoogle Scholar
  67. Lorton D, Schaller J, Lala A, De Nardin E (2000) Chemotactic-like receptors and Abeta peptide induced responses in Alzheimer’s disease. Neurobiol Aging 21(3):463–473PubMedGoogle Scholar
  68. Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp Neurol 171(1):29–45. doi: 10.1006/exnr.2001.7732 PubMedGoogle Scholar
  69. Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE (2009) Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J Neurosci 29(13):4252–4262. doi: 10.1523/JNEUROSCI.5572-08.2009 PubMedCentralPubMedGoogle Scholar
  70. McDonald DR, Bamberger ME, Combs CK, Landreth GE (1998) beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci 18(12):4451–4460PubMedGoogle Scholar
  71. 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):195–200PubMedGoogle Scholar
  72. Methner A, Hermey G, Schinke B, Hermans-Borgmeyer I (1997) A novel G protein-coupled receptor with homology to neuropeptide and chemoattractant receptors expressed during bone development. Biochem Biophys Res Commun 233(2):336–342. doi: 10.1006/bbrc.1997.6455 PubMedGoogle Scholar
  73. Michaud JP, Halle M, Lampron A, Theriault P, Prefontaine P, Filali M, Tribout-Jover P, Lanteigne AM, Jodoin R, Cluff C, Brichard V, Palmantier R, Pilorget A, Larocque D, Rivest S (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci U S A 110(5):1941–1946. doi: 10.1073/pnas.1215165110 PubMedCentralPubMedGoogle Scholar
  74. Mildner A, Schlevogt B, Kierdorf K, Bottcher C, Erny D, Kummer MP, Quinn M, Bruck W, Bechmann I, Heneka MT, Priller J, Prinz M (2011) Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci 31(31):11159–11171. doi: 10.1523/JNEUROSCI.6209-10.2011 PubMedGoogle Scholar
  75. Minghetti L, Ajmone-Cat MA, De Berardinis MA, De Simone R (2005) Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Brain Res Rev 48(2):251–256. doi: 10.1016/j.brainresrev.2004.12.015 PubMedGoogle Scholar
  76. Moore KJ, El Khoury J, Medeiros LA, Terada K, Geula C, Luster AD, Freeman MW (2002) A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. J Biol Chem 277(49):47373–47379. doi: 10.1074/jbc.M208788200 PubMedGoogle Scholar
  77. Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB (2014) Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 8:112. doi: 10.3389/fncel.2014.00112 PubMedCentralPubMedGoogle Scholar
  78. Mulder SD, Veerhuis R, Blankenstein MA, Nielsen HM (2012) The effect of amyloid associated proteins on the expression of genes involved in amyloid-beta clearance by adult human astrocytes. Exp Neurol 233(1):373–379. doi: 10.1016/j.expneurol.2011.11.001 PubMedGoogle Scholar
  79. Origlia N, Bonadonna C, Rosellini A, Leznik E, Arancio O, Yan SS, Domenici L (2010) Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. J Neurosci 30(34):11414–11425. doi: 10.1523/JNEUROSCI.2127-10.2010 PubMedCentralPubMedGoogle Scholar
  80. Pan XD, Zhu YG, Lin N, Zhang J, Ye QY, Huang HP, Chen XC (2011) Microglial phagocytosis induced by fibrillar beta-amyloid is attenuated by oligomeric beta-amyloid: implications for Alzheimer’s disease. Mol Neurodegener 6:45. doi: 10.1186/1750-1326-6-45 PubMedCentralPubMedGoogle Scholar
  81. Paresce DM, Ghosh RN, Maxfield FR (1996) Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 17(3):553–565PubMedGoogle Scholar
  82. Peng L, Yu Y, Liu J, Li S, He H, Cheng N, Ye RD (2014) The Chemerin Receptor CMKLR1 is a Functional Receptor for Amyloid-beta Peptide. J Alzheimers Dis. doi: 10.3233/JAD-141227 Google Scholar
  83. Perez A, Wright MB, Maugeais C, Braendli-Baiocco A, Okamoto H, Takahashi A, Singer T, Mueller L, Niesor EJ (2010) MARCO, a macrophage scavenger receptor highly expressed in rodents, mediates dalcetrapib-induced uptake of lipids by rat and mouse macrophages. Toxicol In Vitro 24(3):745–750. doi: 10.1016/j.tiv.2010.01.002 PubMedGoogle Scholar
  84. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344PubMedGoogle Scholar
  85. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 29(38):11982–11992. doi: 10.1523/JNEUROSCI.3158-09.2009 PubMedCentralPubMedGoogle Scholar
  86. Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE (2010) Deletion of CD14 attenuates Alzheimer’s disease pathology by influencing the brain’s inflammatory milieu. J Neurosci 30(46):15369–15373. doi: 10.1523/JNEUROSCI.2637-10.2010 PubMedCentralPubMedGoogle Scholar
  87. Regland B, Gottfries CG (1992) The role of amyloid beta-protein in Alzheimer’s disease. Lancet 340(8817):467–469PubMedGoogle Scholar
  88. Reichert F, Rotshenker S (2003) Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis in microglia and macrophages. Neurobiol Dis 12(1):65–72PubMedGoogle Scholar
  89. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ (2012) Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 52:179–197. doi: 10.1146/annurev.pharmtox.010909.105800 PubMedCentralPubMedGoogle Scholar
  90. Richard KL, Filali M, Prefontaine P, Rivest S (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. J Neurosci 28(22):5784–5793. doi: 10.1523/JNEUROSCI.1146-08.2008 PubMedGoogle Scholar
  91. Savill J, Hogg N, Ren Y, Haslett C (1992) Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J Clin Invest 90(4):1513–1522. doi: 10.1172/JCI116019 PubMedCentralPubMedGoogle Scholar
  92. Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, Mantua V, Mecocci P, Pani L, Winblad B, Kivipelto M (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275(3):251–283. doi: 10.1111/joim.12191 PubMedGoogle Scholar
  93. Schwartz M, Kipnis J, Rivest S, Prat A (2013) How do immune cells support and shape the brain in health, disease, and aging? J Neurosci 33(45):17587–17596. doi: 10.1523/JNEUROSCI.3241-13.2013 PubMedCentralPubMedGoogle Scholar
  94. Selbie LA, Hill SJ (1998) G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways. Trends Pharmacol Sci 19(3):87–93PubMedGoogle Scholar
  95. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766PubMedGoogle Scholar
  96. Serpell LC (2000) Alzheimer’s amyloid fibrils: structure and assembly. Biochim Biophys Acta 1502(1):16–30PubMedGoogle Scholar
  97. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49(4):489–502. doi: 10.1016/j.neuron.2006.01.022 PubMedGoogle Scholar
  98. Slowik A, Merres J, Elfgen A, Jansen S, Mohr F, Wruck CJ, Pufe T, Brandenburg LO (2012) Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE)—and amyloid beta 1-42-induced signal transduction in glial cells. Mol Neurodegener 7:55. doi: 10.1186/1750-1326-7-55 PubMedCentralPubMedGoogle Scholar
  99. Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, Kim HD, Tahara K, Lalonde R, Fukuchi K (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8:92. doi: 10.1186/1742-2094-8-92 PubMedCentralPubMedGoogle Scholar
  100. Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–161. doi: 10.1038/ni.1836 PubMedCentralPubMedGoogle Scholar
  101. Streit WJ, Walter SA, Pennell NA (1999) Reactive microgliosis. Prog Neurobiol 57(6):563–581PubMedGoogle Scholar
  102. Syvaranta S, Alanne-Kinnunen M, Oorni K, Oksjoki R, Kupari M, Kovanen PT, Helske-Suihko S (2014) Potential pathological roles for oxidized low-density lipoprotein and scavenger receptors SR-AI, CD36, and LOX-1 in aortic valve stenosis. Atherosclerosis 235(2):398–407. doi: 10.1016/j.atherosclerosis.2014.05.933 PubMedGoogle Scholar
  103. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129(Pt 11):3006–3019. doi: 10.1093/brain/awl249 PubMedCentralPubMedGoogle Scholar
  104. Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, Tsuchiya D, Chishiro S, Saeki M, Taniguchi T, Shimohama S, Tooyama I (2007) Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett 581(3):475–478. doi: 10.1016/j.febslet.2007.01.009 PubMedGoogle Scholar
  105. Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S (2010) Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci U S A 107(48):20816–20821. doi: 10.1073/pnas.1005888107 PubMedCentralPubMedGoogle Scholar
  106. Thathiah A, De Strooper B (2011) The role of G protein-coupled receptors in the pathology of Alzheimer’s disease. Nat Rev Neurosci 12(2):73–87. doi: 10.1038/nrn2977 PubMedGoogle Scholar
  107. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283(44):29615–29619. doi: 10.1074/jbc.R800019200 PubMedCentralPubMedGoogle Scholar
  108. Tiffany HL, Lavigne MC, Cui YH, Wang JM, Leto TL, Gao JL, Murphy PM (2001) Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain. J Biol Chem 276(26):23645–23652. doi: 10.1074/jbc.M101031200 PubMedGoogle Scholar
  109. Toyn JH, Ahlijanian MK (2014) Interpreting Alzheimer’s disease clinical trials in light of the effects on amyloid-beta. Alzheimers Res Ther 6(2):14. doi: 10.1186/alzrt244 PubMedGoogle Scholar
  110. Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 37(2):289–305. doi: 10.1016/j.biocel.2004.07.009 PubMedGoogle Scholar
  111. Udan ML, Ajit D, Crouse NR, Nichols MR (2008) Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. J Neurochem 104(2):524–533. doi: 10.1111/j.1471-4159.2007.05001.x PubMedGoogle Scholar
  112. Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, Stewart FR, Piccio L, Colonna M, Holtzman DM (2014) Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 9:20. doi: 10.1186/1750-1326-9-20 PubMedCentralPubMedGoogle Scholar
  113. Verdier Y, Penke B (2004) Binding sites of amyloid beta-peptide in cell plasma membrane and implications for Alzheimer’s disease. Curr Protein Pept Sci 5(1):19–31PubMedGoogle Scholar
  114. Vodopivec I, Galichet A, Knobloch M, Bierhaus A, Heizmann CW, Nitsch RM (2009) RAGE does not affect amyloid pathology in transgenic ArcAbeta mice. Neurodegener Dis 6(5–6):270–280. doi: 10.1159/000261723 PubMedGoogle Scholar
  115. 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-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. J Immunol 185(10):6338–6347. doi: 10.4049/jimmunol.1001765 PubMedGoogle Scholar
  116. Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem 20(6):947–956. doi: 10.1159/000110455 PubMedGoogle Scholar
  117. Wang CY, Wang ZY, Xie JW, Cai JH, Wang T, Xu Y, Wang X, An L (2014) CD36 upregulation mediated by intranasal LV-NRF2 treatment mitigates hypoxia-induced progression of Alzheimer’s-like pathogenesis. Antioxid Redox Signal. doi: 10.1089/ars.2014.5845 Google Scholar
  118. Wilkinson K, El Khoury J (2012) Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer’s disease. Int J Alzheimers Dis 2012:489456. doi: 10.1155/2012/489456 PubMedCentralPubMedGoogle Scholar
  119. Wilkinson B, Koenigsknecht-Talboo J, Grommes C, Lee CY, Landreth G (2006) Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia. J Biol Chem 281(30):20842–20850. doi: 10.1074/jbc.M600627200 PubMedGoogle Scholar
  120. Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D (2003) Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198(7):977–985. doi: 10.1084/jem.20030382 PubMedCentralPubMedGoogle Scholar
  121. Wittamer V, Gregoire F, Robberecht P, Vassart G, Communi D, Parmentier M (2004) The C-terminal nonapeptide of mature chemerin activates the chemerin receptor with low nanomolar potency. J Biol Chem 279(11):9956–9962. doi: 10.1074/jbc.M313016200 PubMedGoogle Scholar
  122. Wu B, Ueno M, Kusaka T, Miki T, Nagai Y, Nakagawa T, Kanenishi K, Hosomi N, Sakamoto H (2013) CD36 expression in the brains of SAMP8. Arch Gerontol Geriatr 56(1):75–79. doi: 10.1016/j.archger.2012.07.007 PubMedGoogle Scholar
  123. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12(9):1005–1015. doi: 10.1038/nm1484 PubMedGoogle Scholar
  124. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7(5):612–618. doi: 10.1038/87945 PubMedGoogle Scholar
  125. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9(4):453–457. doi: 10.1038/nm838 PubMedGoogle Scholar
  126. Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT (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(48):17321–17331. doi: 10.1523/JNEUROSCI.1569-12.2012 PubMedGoogle Scholar
  127. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382(6593):685–691. doi: 10.1038/382685a0 PubMedGoogle Scholar
  128. Yang CN, Shiao YJ, Shie FS, Guo BS, Chen PH, Cho CY, Chen YJ, Huang FL, Tsay HJ (2011) Mechanism mediating oligomeric Abeta clearance by naive primary microglia. Neurobiol Dis 42(3):221–230. doi: 10.1016/j.nbd.2011.01.005 PubMedGoogle Scholar
  129. Yazawa H, Yu ZX, Le Takeda Y, Gong W, Ferrans VJ, Oppenheim JJ, Li CC, Wang JM (2001) Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages. FASEB J 15(13):2454–2462. doi: 10.1096/fj.01-0251com PubMedGoogle Scholar
  130. Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev 61(2):119–161. doi: 10.1124/pr.109.001578 PubMedCentralPubMedGoogle Scholar
  131. Yu Y, Liu J, Li SQ, Peng L, Ye RD (2014) Serum amyloid a differentially activates microglia and astrocytes via the PI3 K pathway. J Alzheimers Dis 38(1):133–144. doi: 10.3233/JAD-130818 PubMedGoogle Scholar
  132. Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Rasool S, Glabe CG, Ehrhart J, Bickford P, Mori T, Obregon D, Town T, Tan J (2011) CD45 deficiency drives amyloid-beta peptide oligomers and neuronal loss in Alzheimer’s disease mice. J Neurosci 31(4):1355–1365. doi: 10.1523/JNEUROSCI.3268-10.2011 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.School of PharmacyShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of PharmacologyUniversity of Illinois College of MedicineChicagoUSA

Personalised recommendations