6,241
Views
377
CrossRef citations to date
0
Altmetric
REVIEW

Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease

, &
Pages 307-321 | Received 02 Mar 2013, Accepted 07 Aug 2013, Published online: 12 Sep 2013

References

  • Fischer P, Zehetmayer S, Jungwirth S, Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord 2008;25:501–7.
  • Hoyer S. Age as risk factor for sporadic dementia of the Alzheimer type? Ann N Y Acad Sci 1994;719:248–56.
  • Arshavsky YI. Why Alzheimer's disease starts with a memory impairment: neurophysiological insight. J Alzheimers Dis 2010;20(1):5–16.
  • Caselli RJ, Beach TG, Yaari R, Reiman EM. Alzheimer's disease a century later. J Clin Psychiatry 2006;67:1784–800.
  • Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992;8:159–68.
  • Goedert M, Jakes R, Crowther RA, The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci USA 1993;90:5066–70.
  • Iijima-Ando K, Hearn SA, Granger L, Overexpression of neprilysin reduces Alzheimer amyloid-beta42 (Aβ-42)-induced neuron loss and intraneuronal Aβ-42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. J Biol Chem 2008;283(27):19066–76.
  • Zhiyou C, Yong Y, Shanquan S, Upregulation of BACE1 and beta-amyloid protein mediated by chronic cerebral hypoperfusion contributes to cognitive impairment and pathogenesis of Alzheimer's disease. Neurochem Res 2009;34(7):1226–35.
  • Finder VH. Alzheimer's disease: a general introduction and pathomechanism. J Alzheimers Dis 2010;22(Suppl 3):5–19.
  • Sisodia SS, Price DL. Role of the beta-amyloid protein in Alzheimer's disease. Faseb J 1995;9:366–70.
  • Weiner MF, Hynan LS, Rossetti H, The relationship of cardiovascular risk factors to Alzheimer disease in Choctaw Indians. Am J Geriatr Psychiatry 2011;19:423–9.
  • Wint D. Depression: a shared risk factor for cardiovascular and Alzheimer disease. Cleve Clin J Med 2011;78(Suppl 1):S44–6.
  • Irie F, Fitzpatrick AL, Lopez OL, Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol 2008;65:89–93.
  • DeCarli CS. When two are worse than one: stroke and Alzheimer disease. Neurology 2006;67:1326–7.
  • Honig LS, Tang MX, Albert S, Stroke and the risk of Alzheimer disease. Arch Neurol 2003;60:1707–12.
  • Koepsell TD, Kurland BF, Harel O, Education, cognitive function, and severity of neuropathology in Alzheimer disease. Neurology 2008;70(19 Pt 2):1732–9.
  • Roe CM, Xiong C, Miller JP, Morris JC. Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis. Neurology 2007;68:223–8.
  • Maynard CJ, Cappai R, Volitakis I, Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology. J Inorg Biochem 2006;100:952–62.
  • Placanica L, Zhu L, Li YM. Gender- and age-dependent gamma-secretase activity in mouse brain and its implication in sporadic Alzheimer disease. PLoS One 2009;4: e5088.
  • Dubinina EE, Kovrugina SV, Konovalov PV. The factors of oxidative stress in neurodegenerative diseases (vascular dementia, Alzheimer disease). Adv Gerontol 2007;20:109–13.
  • Gustafson D, Rothenberg E, Blennow K, An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003;163:1524–8.
  • Kalaria RN. Neurodegenerative disease: diabetes, microvascular pathology and Alzheimer disease. Nat Rev Neurol 2009;5:305–6.
  • Schwab C, McGeer PL. Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis 2008;13:359–69.
  • Perlmutter LS, Scott SA, Barron E, Chui HC. MHC class II-positive microglia in human brain: association with Alzheimer lesions. J Neurosci Res 1992;33:549–58.
  • Rozemuller JM, van der Valk P, Eikelenboom P. Activated microglia and cerebral amyloid deposits in Alzheimer's disease. Res Immunol 1992;143:646–9.
  • Ard MD, Cole GM, Wei J, Scavenging of Alzheimer's amyloid beta-protein by microglia in culture. J Neurosci Res 1996;43:190–202.
  • Grathwohl SA, Kalin RE, Bolmont T, Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 2009;12:1361–3.
  • Majumdar A, Capetillo-Zarate E, Cruz D, Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Mol Biol Cell 2011;22:1664–76.
  • Bianca VD, Dusi S, Bianchini E, Beta-amyloid activates the O-2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease. J Biol Chem 1999;274:15493–9.
  • Coraci IS, Husemann J, Berman JW, 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 2002;160:101–12.
  • Doi Y, Mizuno T, Maki Y, Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Am J Pathol 2009;175:2121–32.
  • Jana M, Palencia CA, Pahan K. Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J Immunol 2008;181:7254–62.
  • Muehlhauser F, Liebl U, Kuehl S, Aggregation-dependent interaction of the Alzheimer's beta-amyloid and microglia. Clin Chem Lab Med 2001;39:313–6.
  • Zaheer S, Thangavel R, Wu Y, Enhanced expression of glial maturation factor correlates with glial activation in the brain of triple transgenic Alzheimer's disease mice. Neurochem Res 2013;38:218–25.
  • Lee DC, Rizer J, Hunt JB, Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology. Neuropathol Appl Neurobiol 2013;39:69–85.
  • Rosi S, Pert CB, Ruff MR, Chemokine receptor 5 antagonist D-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease. Neuroscience 2005;134: 671–6.
  • Lee JK, Schuchman EH, Jin HK, Bae JS. Soluble CCL5 derived from bone marrow-derived mesenchymal stem cells and activated by amyloid beta ameliorates Alzheimer's disease in mice by recruiting bone marrow-induced microglia immune responses. Stem Cells 2012;30:1544–55.
  • Solito E, Sastre M. Microglia function in Alzheimer's disease. Front Pharmacol 2012;3:14.
  • Weitz TM, Town T. Microglia in Alzheimer's disease: it's all about context. Int J Alzheimer's Dis 2012; 2012: 314185.
  • Imamoto K. Origin of microglia: cell transformation from blood monocytes into macrophagic ameboid cells and microglia. Prog Clin Biol Res 1981;59A:125–39.
  • Marin-Teva JL, Almendros A, Calvente R, Proliferation of actively migrating ameboid microglia in the developing quail retina. Anat Embryol (Berl) 1999;200:289–300.
  • Glenn JA, Booth PL, Thomas WE. Pinocytotic activity in ramified microglia. Neurosci Lett 1991;123:27–31.
  • Wierzba-Bobrowicz T, Gwiazda E, Kosno-Kruszewska E, Morphological analysis of active microglia–rod and ramified microglia in human brains affected by some neurological diseases (SSPE, Alzheimer's disease and Wilson's disease). Folia Neuropathol 2002;40:125–31.
  • Lee S, Lee J, Kim S, A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia. J Immunol 2007;179:3231–41.
  • Mertsch K, Hanisch UK, Kettenmann H, Schnitzer J. Characterization of microglial cells and their response to stimulation in an organotypic retinal culture system. J Comp Neurol 2001;431:217–27.
  • Slepko N, Minghetti L, Polazzi E, Reorientation of prostanoid production accompanies “activation” of adult microglial cells in culture. J Neurosci Res 1997;49:292–300.
  • Choi J, Ifuku M, Noda M, Guilarte TR. Translocator protein (18 kDa)/peripheral benzodiazepine receptor-specific ligands induce microglia functions consistent with an activated state. Glia 2011;59:219–30.
  • Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 2003;304:1–7.
  • Zhang SC, Goetz BD, Carre JL, Duncan ID. Reactive microglia in dysmyelination and demyelination. Glia 2001;34:101–9.
  • Kraft AD, Harry GJ. Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int J Environ Res Public Health 2011;8:2980–3018.
  • Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004;1:14.
  • Harry GJ, Kraft AD. Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert Opin Drug Metab Toxicol 2008;4:1265–77.
  • Krause DL, Muller N. Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer's disease. Int J Alzheimer's Dis 2010;2010. doi: 10.4061/2010/732806.
  • Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 2009;4:47.
  • Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: the role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 2006;6:237–45.
  • Culbert AA, Skaper SD, Howlett DR, MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. J Biol Chem 2006;281:23658–67.
  • Rogers J, Mastroeni D, Leonard B, Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int Rev Neurobiol 2007;82:235–46.
  • Zheng Z, White C, Lee J, Altered microglial copper homeostasis in a mouse model of Alzheimer's disease. J Neurochem 2010;114:1630–8.
  • McGeer EG, McGeer PL. Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy. J Alzheimers Dis 2010;19:355–61.
  • Szczepanik AM, Funes S, Petko W, Ringheim GE. IL-4, IL-10 and IL-13 modulate A beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 2001;113:49–62.
  • Veerhuis R, Janssen I, De Groot CJ, Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor. Exp Neurol 1999;160:289–99.
  • Szczepanik AM, Rampe D, Ringheim GE. Amyloid-beta peptide fragments p3 and p4 induce pro-inflammatory cytokine and chemokine production in vitro and in vivo. J Neurochem 2001;77:304–17.
  • Sochocka M, Koutsouraki ES, Gasiorowski K, Leszek J. Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer's disease: new approach to therapy. CNS Neurol Disord Drug Targets 2013.
  • Li J, Yang JY, Yao XC, Oligomeric Aβ-induced microglial activation is possibly mediated by NADPH oxidase. Neurochem Res 2013;38:443–52.
  • Liu Y, Qin L, Wilson BC, Inhibition by naloxone stereoisomers of beta-amyloid peptide (1–42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons. J Pharmacol Exp Ther 2002;302:1212–9.
  • Billiau A. Interferon beta in the cytokine network: an anti-inflammatory pathway. Mult Scler 1995;1(Suppl 1):S2–4.
  • Lisak RP, Bealmear B, Nedelkoska L, Benjamins JA. Secretory products of central nervous system glial cells induce Schwann cell proliferation and protect from cytokine-mediated death. J Neurosci Res 2006;83(8):1425–31.
  • Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011;1813:878–88.
  • Standiford TJ. Anti-inflammatory cytokines and cytokine antagonists. Curr Pharm Des 2000;6:633–49.
  • Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol 2005;71:317–41.
  • Seymour RM, Henderson B. Pro-inflammatory–anti-inflammatory cytokine dynamics mediated by cytokine-receptor dynamics in monocytes. IMA J Math Appl Med Biol 2001;18:159–92.
  • Tilg H, Trehu E, Atkins MB, Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 1994;83:113–8.
  • Zhao W, Xie W, Xiao Q, Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 2006;99:1176–87.
  • Morganti-Kossmann MC, Kossmann T, Wahl SM. Cytokines and neuropathology. Trends Pharmacol Sci 1992;13:286–91.
  • Tuttolomondo A, Di Raimondo D, di Sciacca R, Inflammatory cytokines in acute ischemic stroke. Curr Pharm Des 2008;14:3574–89.
  • Gambi F, Reale M, Iarlori C, Alzheimer patients treated with an AchE inhibitor show higher IL-4 and lower IL-1 beta levels and expression in peripheral blood mononuclear cells. J Clin Psychopharmacol 2004;24:314–21.
  • Ojala J, Alafuzoff I, Herukka SK, Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients. Neurobiol Aging 2009;30:198–209.
  • Lampron A, Pimentel-Coelho PM, Rivest S. Migration of bone marrow-derived cells into the CNS in models of neurodegeneration. J Comp Neurol 2013. doi: 10.1002/cne.23363
  • McLarnon JG. Microglial chemotactic signaling factors in Alzheimer's disease. Am J Neurodegener Dis 2012;1:199–204.
  • Zhao H, Wang SL, Qian L, Diammonium glycyrrhizinate attenuates Aβ(1–42)-induced neuroinflammation and regulates MAPK and NF-κB pathways in vitro and in vivo. CNS Neurosci Ther 2013;19(2):117–24.
  • Brandenburg LO, Konrad M, Wruck CJ, 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 2010;113:749–60.
  • Feng Y, Li L, Sun XH. Monocytes and Alzheimer's disease. Neurosci Bull 2011;27:115–22.
  • Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 2008;28:8354–60.
  • Yang CN, Shiao YJ, Shie FS, Mechanism mediating oligomeric Aβ clearance by naive primary microglia. Neurobiol Dis 2011;42:221–30.
  • El Khoury J, Hickman SE, Thomas CA, Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 1996;382:716–9.
  • Alarcon R, Fuenzalida C, Santibanez M, von Bernhardi R. 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. 2005;280:30406–15.
  • Kunjathoor VV, Tseng AA, Medeiros LA, Beta-amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins. J Neuroinflammation 2004;1:23.
  • Paresce DM, Ghosh RN, Maxfield FR. Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 1996;17:553–65.
  • Chung H, Brazil MI, Irizarry MC, Uptake of fibrillar beta-amyloid by microglia isolated from MSR-A (type I and type II) knockout mice. Neuroreport 2001;12:1151–4.
  • Huang F, Buttini M, Wyss-Coray T, Elimination of the class A scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors. Am J Pathol 1999;155:1741–7.
  • Park L, Zhou J, Zhou P, Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc Natl Acad Sci USA 2013;110:3089–94.
  • Khalil A, Berrougui H, Pawelec G, Fulop T. Impairment of the ABCA1 and SR-BI-mediated cholesterol efflux pathways and HDL anti-inflammatory activity in Alzheimer's disease. Mech Ageing Dev 2012;133:20–9.
  • Park L, Wang G, Zhou P, Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci USA 2011;108:5063–8.
  • Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci USA 2010;107:20816–21.
  • El Khoury JB, Moore KJ, Means TK, CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003;197:1657–66.
  • Husemann J, Loike JD, Kodama T, Silverstein SC. Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar beta-amyloid. J Neuroimmunol 2001; 114:142–50.
  • Moore KJ, El Khoury J, Medeiros LA, A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. J Biol Chem 2002;277:47373–9.
  • Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci USA 2010;107:20816–21.
  • Nakamura K, Ohya W, Funakoshi H, Possible role of scavenger receptor SRCL in the clearance of amyloid-beta in Alzheimer's disease. J Neurosci Res 2006;84:874–90.
  • Wang C, Sun B, Zhou Y, Cathepsin B degrades amyloid-beta in mice expressing wild-type human amyloid precursor protein. J Biol Chem 2012;287:39834–41.
  • Hui L, Chen X, Geiger JD. Endolysosome involvement in LDL cholesterol-induced Alzheimer's disease-like pathology in primary cultured neurons. Life Sci 2012;91:1159–68.
  • Cataldo AM, Thayer CY, Bird ED, Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer's disease: evidence for a neuronal origin. Brain Res 1990;513:181–92.
  • Sun B, Zhou Y, Halabisky B, Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron 2008;60:247–57.
  • Zerovnik E. The emerging role of cystatins in Alzheimer's disease. Bioessays 2009;31:597–9.
  • Arnaud LT, Myeku N, Figueiredo-Pereira ME. Proteasome-caspase-cathepsin sequence leading to tau pathology induced by prostaglandin J2 in neuronal cells. J Neurochem 2009;110:328–42.
  • Gan L, Ye S, Chu A, Identification of cathepsin B as a mediator of neuronal death induced by Aβ-activated microglial cells using a functional genomics approach. J Biol Chem 2004;279:5565–72.
  • Wirths O, Breyhan H, Marcello A, Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging 2010;31:747–57.
  • Kingham PJ, Pocock JM. Microglial secreted cathepsin B induces neuronal apoptosis. J Neurochem 2001;76:1475–84.
  • Bell RD, Zlokovic BV. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. Acta Neuropathol 2009;118:103–13.
  • Carrano A, Hoozemans JJ, van der Vies SM, Amyloid beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal 2011;15:1167–78.
  • Pflanzner T, Kuhlmann CR, Pietrzik CU. Blood-brain-barrier models for the investigation of transporter- and receptor-mediated amyloid-beta clearance in Alzheimer's disease. Curr Alzheimer Res 2010;7:578–90.
  • Bolton SJ, Perry VH. Differential blood-brain barrier breakdown and leukocyte recruitment following excitotoxic lesions in juvenile and adult rats. Exp Neurol 1998; 154:231–40.
  • Jensen MB, Finsen B, Zimmer J. Morphological and immunophenotypic microglial changes in the denervated fascia dentata of adult rats: correlation with blood-brain barrier damage and astroglial reactions. Exp Neurol 1997;143:103–16.
  • Persidsky Y, Ghorpade A, Rasmussen J, Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis. Am J Pathol 1999;155:1599–611.
  • Ryu JK, McLarnon JG. A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer's disease brain. J Cell Mol Med 2009;13:2911–25.
  • Giri R, Shen Y, Stins M, Beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am J Physiol Cell Physiol 2000;279:C1772–81.
  • Jeynes B, Provias J. Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. Curr Alzheimer Res 2008;5:432–7.
  • Willis CL. Glia-induced reversible disruption of blood-brain barrier integrity and neuropathological response of the neurovascular unit. Toxicol Pathol 2011;39:172–85.
  • Lee SH, Takahashi M, Honke K, Loss of core fucosylation of low-density lipoprotein receptor-related protein-1 impairs its function, leading to the upregulation of serum levels of insulin-like growth factor-binding protein 3 in Fut8−/− mice. J Biochem 2006;139:391–8.
  • Ito S, Ueno T, Ohtsuki S, Terasaki T. Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-beta peptide(1–40) in mouse: involvement of an LRP-1-independent pathway. J Neurochem 2010;113:1356–63.
  • Pflanzner T, Janko MC, Andre-Dohmen B, LRP1 mediates bidirectional transcytosis of amyloid-beta across the blood-brain barrier. Neurobiol Aging 2010;32:2323, e2321–2311.
  • Deane R, Sagare A, Zlokovic BV. The role of the cell surface LRP and soluble LRP in blood-brain barrier Aβ clearance in Alzheimer's disease. Curr Pharm Des 2008;14:1601–5.
  • Donahue JE, Flaherty SL, Johanson CE, RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. Acta Neuropathol 2006;112:405–15.
  • von Arnim CA, Kinoshita A, Peltan ID, The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem 2005;280:17777–85.
  • Marks N, Berg MJ. BACE and gamma-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis. Neurochem Res 2010;35:181–210.
  • Jaeger LB, Dohgu S, Sultana R, Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease. Brain Behav Immun 2009;23:507–7.
  • Alexiou P, Chatzopoulou M, Pegklidou K, Demopoulos VJ. RAGE: a multi-ligand receptor unveiling novel insights in health and disease. Curr Med Chem 2010;17:2232–52.
  • Kang R, Tang D, Loze MT, Zeh HJ. Apoptosis to autophagy switch triggered by the MHC class III-encoded receptor for advanced glycation endproducts (RAGE). Autophagy 2011;7:91–3.
  • Deane R, Zlokovic BV. Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res 2007;4:191–7.
  • Li M, Shang DS, Zhao WD, Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier. J Immunol 2009;182:5778–88.
  • Askarova S, Yang X, Sheng W, Role of Aβ-receptor for advanced glycation endproducts interaction in oxidative stress and cytosolic phospholipase A(2) activation in astrocytes and cerebral endothelial cells. Neuroscience 2011;199:375–85.
  • Candela P, Gosselet F, Saint-Pol J, Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein. J Alzheimers Dis 2010;22:849–59.
  • Chen X, Walker DG, Schmidt AM, RAGE: a potential target for Aβ-mediated cellular perturbation in Alzheimer's disease. Curr Mol Med 2007;7:735–42.
  • Lue LF, Yan SD, Stern DM, Walker DG. Preventing activation of receptor for advanced glycation endproducts in Alzheimer's disease. Curr Drug Targets CNS Neurol Disord 2005;4:249–66.
  • Kim HY, Han SH. Matrix metalloproteinases in cerebral ischemia. J Clin Neurol 2006;2:163–70.
  • Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002;39:279–91.
  • Rosenberg GA, Cunningham LA, Wallace J, Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 2001;893:104–12.
  • Tian W, Kyriakides TR. Matrix metalloproteinase-9 deficiency leads to prolonged foreign body response in the brain associated with increased IL-1beta levels and leakage of the blood-brain barrier. Matrix Biol 2009;28:148–59.
  • Lee KW, Kim JB, Seo JS, Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem 2009;108:165–75.
  • Yamada T, Yoshiyama Y, Sato H, White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues. Acta Neuropathol 1995;90:421–4.
  • Yoshiyama Y, Sato H, Seiki M, Expression of the membrane-type 3 matrix metalloproteinase (MT3-MMP) in human brain tissues. Acta Neuropathol 1998;96:347–50.
  • Lee EO, Kang JL, Chong YH. The amyloid-beta peptide suppresses transforming growth factor-beta1-induced matrix metalloproteinase-2 production via Smad7 expression in human monocytic THP-1 cells. J Biol Chem 2005;280:7845–53.
  • Walker DG, Link J, Lue LF, Gene expression changes by amyloid beta peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. J Leukoc Biol 2006;79:596–610.
  • Lorenzl S, Albers DS, Relkin N, Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease. Neurochem Int 2003;43:191–6.
  • Stein VM, Puff C, Genini S, Variations on brain microglial gene expression of MMPs, RECK, and TIMPs in inflammatory and non-inflammatory diseases in dogs. Vet Immunol Immunopathol 2011;144:17–26.
  • Conant K, McArthur JC, Griffin DE, Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia. Ann Neurol 1999;46:391–8.
  • Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002;39:279–91.
  • Miners JS, Baig S, Palmer J, Aβ-degrading enzymes in Alzheimer's disease. Brain Pathol 2008;18:240–52.
  • Hanson LR, Hafez D, Svitak AL, Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice. J Mol Neurosci 2011;43:424–7.
  • Eckman EA, Eckman CB. Aβ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochem Soc Trans 2005;33(Pt 5): 1101–5.
  • Miners JS, Morris S, Love S, Kehoe PG. Accumulation of insoluble amyloid-beta in down's syndrome is associated with increased BACE-1 and neprilysin activities. J Alzheimers Dis 2011;23:101–8.
  • Wang S, Wang R, Chen L, Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain. J Neurochem 2010;115:47–57.
  • Liu Y, Liu L, Lu S, Impaired amyloid beta-degrading enzymes in brain of streptozotocin-induced diabetic rats. J Endocrinol Invest 2011;34:26–31.
  • Zou K, Michikawa M. Angiotensin-converting enzyme as a potential target for treatment of Alzheimer's disease: inhibition or activation? Rev Neurosci 2008;19:203–12.
  • Miners JS, van Helmond Z, Kehoe PG, Love S. Changes with age in the activities of beta-secretase and the Aβ-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme. Brain Pathol 2010;20:794–802.
  • Lan X, Xu J, Kiyota T, HIV-1 reduces Aβ-degrading enzymatic activities in primary human mononuclear phagocytes. J Immunol 2011;186:6925–32.
  • Vekrellis K, Ye Z, Qiu WQ, Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci 2000;20:1657–1665.
  • Qiu WQ, Walsh DM, Ye Z, Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998;273:32730–8.
  • Qiu WQ, Ye Z, Kholodenko D, Degradation of amyloid beta-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J Biol Chem 1997;272:6641–6.
  • Houalla T, Levine RL. The isolation and culture of microglia-like cells from the goldfish brain. J Neurosci Methods 2003;131:121–31.
  • Lee JK, Tansey MG. Microglia isolation from adult mouse brain. Methods Mol Biol 2013;1041:17–23.
  • Shimizu E, Kawahara K, Kajizono M, IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1–42) by rat primary type 2 microglia. J Immunol 2008;181: 6503–13.
  • Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 2008;28:8354–60.
  • Spencer B, Rockenstein E, Crews L, Novel strategies for Alzheimer's disease treatment. Expert Opin Biol Ther 2007;7:1853–67.
  • Panchal M, Lazar N, Munoz N, Clearance of amyloid-beta peptide by neuronal and non-neuronal cells: proteolytic degradation by secreted and membrane associated proteases. Curr Neurovasc Res 2007;4:240–51.
  • Choi DS, Wang D, Yu GQ, PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc Natl Acad Sci U S A 2006;103:8215–20.
  • Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 2002;32:1050–60.
  • Standridge JB. Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease. Curr Alzheimer Res 2006;3:95–108.
  • Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 2013;62:90–101.
  • Cai Z, Zhao B, Ratka A. Oxidative stress and beta-amyloid protein in Alzheimer's disease. Neuromolecular Med 2011;13:223–50.
  • Heneka MT, Sastre M, Dumitrescu-Ozimek L, Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2005;2:22.
  • Janelsins MC, Mastrangelo MA, Oddo S, Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation 2005;2:23.
  • Hu J, Akama KT, Krafft GA, Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction, and nitric oxide release. Brain Res 1998;785:195–206.
  • Szczepanik AM, Ringheim GE. IL-10 and glucocorticoids inhibit Aβ (1–42)- and lipopolysaccharide-induced pro-inflammatory cytokine and chemokine induction in the central nervous system. J Alzheimers Dis 2003;5:105–17.
  • Ayasolla K, Khan M, Singh AK, Singh I. Inflammatory mediator and beta-amyloid (25–35)-induced ceramide generation and iNOS expression are inhibited by vitamin E. Free Radic Biol Med 2004;37:325–38.
  • Garcao P, Oliveira CR, Agostinho P. Comparative study of microglia activation induced by amyloid-beta and prion peptides: role in neurodegeneration. J Neurosci Res 2006; 84:182–93.
  • Parvathy S, Rajadas J, Ryan H, Aβ peptide conformation determines uptake and interleukin-1alpha expression by primary microglial cells. Neurobiol Aging 2009;30:1792–804.
  • O'Barr S, Cooper NR. The C5a complement activation peptide increases IL-1beta and IL-6 release from amyloid-beta primed human monocytes: implications for Alzheimer's disease. J Neuroimmunol 2000;109:87–94.
  • Veerhuis R, Van Breemen MJ, Hoozemans JM, Amyloid beta plaque-associated proteins C1q and SAP enhance the Aβ1–42 peptide-induced cytokine secretion by adult human microglia in vitro. Acta Neuropathol 2003;105:135–44.
  • Bachstetter AD, Xing B, de Almeida L, Microglial p38alpha MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ). J Neuroinflammation 2011;8:79.
  • Bach JP, Mengel D, Wahle T, The role of CNI-1493 in the function of primary microglia with respect to amyloid-beta. J Alzheimer's Dis 2011;26:69–80.
  • Suo Z, Tan J, Placzek A, Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40. Brain Res 1998;807(1–2):110–17.
  • Chiarini A, Dal Pra I, Whitfield JF, Armato U. The killing of neurons by beta-amyloid peptides, prions, and pro-inflammatory cytokines. Ital J Anat Embryol 2006;111:221–46.
  • Samuelsson M, Fisher L, Iverfeldt K. Beta-amyloid and interleukin-1beta induce persistent NF-κB activation in rat primary glial cells. Int J Mol Med 2005;16(3):449–53.
  • Zhu Y, Hou H, Nikolic WV, CD45RB is a novel molecular therapeutic target to inhibit Aβ peptide-induced microglial MAPK activation. PLoS One 2008;3:e2135.
  • Maezawa I, Zimin PI, Wulff H, Jin LW. Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem 2011; 286:3693–706.
  • Origlia N, Bonadonna C, Rosellini A, 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 2010; 30:11414–25.
  • Pan XD, Chen XC, Zhu YG, Tripchlorolide protects neuronal cells from microglia-mediated beta-amyloid neurotoxicity through inhibiting NF-κB and JNK signaling. Glia 2009;57:1227–38.
  • Giovannini MG, Scali C, Prosperi C, Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis 2002;11:257–74.
  • Passos GF, Figueiredo CP, Prediger RD, Role of the macrophage inflammatory protein-1alpha/CC chemokine receptor 5 signaling pathway in the neuroinflammatory response and cognitive deficits induced by beta-amyloid peptide. Am J Pathol 2009;175:1586–97.
  • Jekabsone A, Mander PK, Tickler A, Fibrillar beta-amyloid peptide Aβ1–40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflammation 2006;3:24.
  • Zhang DL, Chen YQ, Jiang X, Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice. Neurosci Bull 2009;25:131–7.
  • Quinn J, Kulhanek D, Nowlin J, Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials. Brain Res 2005;1037:209–13.
  • Agostinho P, Cunha RA, Oliveira C. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease. Curr Pharm Des 2010;16:2766–78.
  • Kim CY, Lee C, Park GH, Jang JH. Neuroprotective effect of epigallocatechin-3-gallate against beta-amyloid-induced oxidative and nitrosative cell death via augmentation of antioxidant defense capacity. Arch Pharm Res 2009;32:869–81.
  • Heo HJ, Cho HY, Hong B, Protective effect of 4′,5-dihydroxy-3′,6,7-trimethoxyflavone from Artemisia asiatica against Aβ-induced oxidative stress in PC12 cells. Amyloid 2001;8:194–201.
  • Liew YF, Huang CT, Chou SS, The isolated and combined effects of folic acid and synthetic bioactive compounds against Aβ (25–35)-induced toxicity in human microglial cells. Molecules 2010;15:1632–44.
  • Pan XD, Zhu YG, Lin N, Microglial phagocytosis induced by fibrillar beta-amyloid is attenuated by oligomeric beta-amyloid: implications for Alzheimer's disease. Mol Neurodegener 2011;6:45.
  • Akama KT, Albanese C, Pestell RG, Van Eldik LJ. Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NF-κB-dependent mechanism. Proc Natl Acad Sci USA 1998;95:5795–800.
  • Yan SD, Stern D, Kane MD, RAGE-Aβ interactions in the pathophysiology of Alzheimer's disease. Restor Neurol Neurosci 1998;12:167–73.
  • Milton RH, Abeti R, Averaimo S, CLIC1 function is required for beta-amyloid-induced generation of reactive oxygen species by microglia. J Neurosci 2008;28:11488–99.
  • Yang SG, Wang WY, Ling TJ, Alpha-tocopherol quinone inhibits beta-amyloid aggregation and cytotoxicity, disaggregates preformed fibrils and decreases the production of reactive oxygen species, NO and inflammatory cytokines. Neurochem Int 2010;57:914–22.
  • Abramov AY, Canevari L, Duchen MR. Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 2004;24:565–75.
  • Szaingurten-Solodkin I, Hadad N, Levy R. Regulatory role of cytosolic phospholipase A2alpha in NADPH oxidase activity and in inducible nitric oxide synthase induction by aggregated Aβ1–42 in microglia. Glia 2009;57:1727–40.
  • Velez-Pardo C, Ospina GG, Jimenez del Rio M. Aβ [25–35] peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism: involvement of H2O2, caspase-3, NF-κB, p53 and c-Jun. Neurotoxicology 2002;23:351–65.
  • Walker DG, Lue LF, Beach TG. Increased expression of the urokinase plasminogen-activator receptor in amyloid beta peptide-treated human brain microglia and in AD brains. Brain Res 2002;926:69–79.
  • Lindberg C, Selenica ML, Westlind-Danielsson A, Schultzberg M. Beta-amyloid protein structure determines the nature of cytokine release from rat microglia. J Mol Neurosci 2005;27:1–12.
  • Sondag CM, Dhawan G, Combs CK. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflammation 2009;6:1.
  • Bamberger ME, Landreth GE. Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer's disease. Microsc Res Tech 2001;54:59–70.
  • Patel NS, Paris D, Mathura V, Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease. J Neuroinflammation 2005;2:9.
  • Lindberg C, Hjorth E, Post C, Cytokine production by a human microglial cell line: effects of beta-amyloid and alpha-melanocyte-stimulating hormone. Neurotox Res 2005;8:267–76.
  • Craft JM, Watterson DM, Hirsch E, Van Eldik LJ. Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human beta-amyloid. J Neuroinflammation 2005;2:15.
  • Grzanna R, Phan P, Polotsky A, Ginger extract inhibits beta-amyloid peptide-induced cytokine and chemokine expression in cultured THP-1 monocytes. J Altern Complement Med 2004;10:1009–13.
  • Zaheer A, Zaheer S, Thangavel R, Glia maturation factor modulates beta-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage. Brain Res 2008;1208:192–203.
  • von Bernhardi R, Eugenin J. Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res 2004;1025:186–93.
  • Gan L, Ye S, Chu A, Identification of cathepsin B as a mediator of neuronal death induced by Aβ-activated microglial cells using a functional genomics approach. J Biol Chem 2004;279:5565–72.
  • Samuelsson M, Ramberg V, Iverfeldt K. Alzheimer amyloid-beta peptides block the activation of C/EBPbeta and C/EBPdelta in glial cells. Biochem Biophys Res Commun 2008;370:619–22.
  • Floden AM, Li S, Combs CK. Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. J Neurosci 2005;25:2566–75.
  • Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 2009;29:11982–92.
  • Passos GF, Figueiredo CP, Prediger RD, Involvement of phosphoinositide 3-kinase gamma in the neuro-inflammatory response and cognitive impairments induced by beta-amyloid 1–40 peptide in mice. Brain Behav Immun 2010;24:493–501.
  • Jana M, Jana A, Liu X, Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I κB alpha in anti-inflammatory effect of gemfibrozil in microglia. J Immunol 2007;179:4142–52.
  • Liu YY, Bian JS. Hydrogen sulfide protects amyloid-beta induced cell toxicity in microglia. J Alzheimers Dis 2010;22:1189–200.
  • Lee HS, Jung KK, Cho JY, Neuroprotective effect of curcumin is mainly mediated by blockade of microglial cell activation. Pharmazie 2007;62:937–42.
  • Cordle A, Landreth G. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. J Neurosci 2005; 25:299–307.
  • Fleisher-Berkovich S, Filipovich-Rimon T, Ben-Shmuel S, Distinct modulation of microglial amyloid beta phagocytosis and migration by neuropeptides (i). J Neuroinflammation 2010;7:61.
  • Ralay Ranaivo H, Craft JM, Hu W, Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci 2006;26:662–70.
  • Clarke RM, O'Connell F, Lyons A, Lynch MA. The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-beta1–42 in the rat hippocampus in vivo. Neuropharmacology 2007;52:136–45.
  • Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Aβ deposition, and behavior in APP-tg mice. Glia 2006;53:776–82.
  • Delgado M, Varela N, Gonzalez-Rey E. Vasoactive intestinal peptide protects against beta-amyloid-induced neurodegeneration by inhibiting microglia activation at multiple levels. Glia 2008;56:1091–103.
  • Cornejo F, von Bernhardi R. Role of scavenger receptors in glia-mediated neuroinflammatory response associated with Alzheimer's disease. Mediators Inflamm 2013;2013:895 651.
  • Wilkinson K, El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Int J Alzheimer's Dis 2012;2012:489456.
  • Hughes MM, Field RH, Perry VH, Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrPSc, even upon LPS stimulation. Glia 2010;58:2017–30.
  • Giunta M, Rigamonti AE, Scarpini E, The leukocyte expression of CD36 is low in patients with Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2007;28:515–8.
  • Srivastava RA, Jain JC. Scavenger receptor class B type I expression and elemental analysis in cerebellum and parietal cortex regions of the Alzheimer's disease brain. J Neurol Sci 2002;196:45–52.
  • Nakamura K, Ohya W, Funakoshi H, Possible role of scavenger receptor SRCL in the clearance of amyloid-beta in Alzheimer's disease. J Neurosci Res 2006;84:874–90.
  • Christie RH, Freeman M, Hyman BT. Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer's disease. Am J Pathol 1996;148:399–403.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.