Beta Amyloid Protein Clearance and Microglial Activation

  • Sally A. Frautschy
  • Greg M. Cole
  • March D. Ard


Progression of AD involves a slow accumulation of Aβ peptide deposited extracellularly in the neuropil and vasculature of the brain. Aβ peptides of MW from 4 to 5 kD (Aβ40, Aβ42 or Aβ43) are normally produced by many cells, but the mutations in early onset familial AD (fAD) cause increased production of the rapidly aggregating Aβ1–42 (Borchelt et al. (1997); Younkin (1995)). However, in approximately 95% of cases of AD, there is Aβ accumulation without genetically increased Aβ production. Thus, in the vast majority of AD cases, which arise out of interaction of aging with genetic risk factors, other aspects of Aβ metabolism appear to be important. For example, the increased risk, and earlier onset, of AD from the apolipoprotein (Apo) E4 allele, which is strongest between 65 and 80 years of age, is not associated with increased Aβ production, but rather with reduced Aβ clearance or enhanced amyloid formation. Other potential genetic risk factors for late-onset AD may also influence AD pathogenesis at levels beyond Aβ production, including alpha-2 macroglobulin (Liao et al. 1998), alpha-1 antichymotrypsin (Thome et al. (1995)), interleukin 1 (Nicoll et al. (2000)), and transforming growth factor beta (Luedecking et al. (2000)). Although factors regulating Aβ degradation and clearance have received little attention compared with factors regulating Aβ production associated with early-onset AD genes, there is now a large enough literature to consider the issues.


Microglial Activation Amyloid Precursor Protein Amyloid Plaque Senile Plaque Scavenger Receptor 
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  1. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M (1996). Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271:518–520.PubMedCrossRefGoogle Scholar
  2. 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 21:383–421.PubMedCrossRefGoogle Scholar
  3. Allsop D, Haga S, Haga C, Ikeda S, Mann DM, Ishii T (1989). Early senile plaques in Down’s syndrome brains show a close relationship with cell bodies of neurons. Neuropathol Appl Neurobiol 15:531–542.PubMedCrossRefGoogle Scholar
  4. Ard MD, Cole GM, Wei J, Mehrle AP, Fratkin JD (1996). Scavenging of Alzheimer’s amyloid β-protein by microglia in culture. J Neurosci Res 43:190–202.PubMedCrossRefGoogle Scholar
  5. Backstrom JR, Lim GP, Cullen MJ, Tokes ZA (1996). Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1–40). J Neurosci 16:7910–7919.PubMedGoogle Scholar
  6. BacSkai, BJ, Kajdasz, ST, Christie, RH, Carter, CW, Games, D, Seubert, P, Schenk, D, and Hyman, BT (2001). Imaging of amyloid-deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 7:369–372.PubMedCrossRefGoogle Scholar
  7. Bard F, Cannon C, Barbour R, Burke Rl, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D and Yednock T (2000). Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8), 916–9.PubMedCrossRefGoogle Scholar
  8. Bell MD, López-González R, Lawson L, Hughes D, Fraser I, Gordon S, Perry VH (1994). Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS. J Neurocytol 23:605–613.PubMedCrossRefGoogle Scholar
  9. Benzing WC, Mufson EJ, Armstrong DM (1993). Immunocytochemical distribution of peptidergic and cholinergic fibers in the human amygdala: their depletion in Alzheimer’s disease and morphologic alteration in non-demented elderly with numerous senile plaques. Brain Res 625:125–38.PubMedCrossRefGoogle Scholar
  10. Biere AL, Ostaszewski B, Stimson ER, Hyman BT, Maggio JE, Selkoe DJ (1996). Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J Biol Chem 271:32916–32922.PubMedCrossRefGoogle Scholar
  11. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, et al. Sisodia S (1996). Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta 1 – 42/1–40 ratio in vitro and in vivo. Neuron 17:1005–1013.PubMedCrossRefGoogle Scholar
  12. Borchelt DR, Ratovitski T, Van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945.PubMedCrossRefGoogle Scholar
  13. Bornemann, KD and Staufenbiel, M (2000). Transgenic mouse models of Alzheimer’s disease. Ann N Y Acad Sci 908, 260–266.PubMedCrossRefGoogle Scholar
  14. Brazil MI, Chung H, Maxfield FR (2000). Effects of incorporation of immunoglobuling and complement component C1q on uptake and degradation of Alzheimer’s disease amyloid fibrils by microglia. J Biol Chem 275:16941–7.PubMedCrossRefGoogle Scholar
  15. Breitner JCS, Welsh KA, Helms MJ, Gaskell PC, Gau BA, Roses AD, Vance MAP, Saunders AM, (1995). Delayed onset of Alzheimer’s disease with nonsteroidal antiinflammatory and histamine H2 blocking drugs. Neurobiol Aging 16:523–530.PubMedCrossRefGoogle Scholar
  16. Brown EO, Sundstrom SA, Komm BS, Yi Z, Teuscher C, Lyttle CR (1990). Progesterone regulation of estradiol-induced rat uterine secretory protein, complement C3. Biol Reprod 42:713–719.PubMedCrossRefGoogle Scholar
  17. Bruce-Keller AJ, Keelking JN, Huang FF, Camondola S, Mattson MP (2000). Antiinflammatory effects of estrogen on microglial activation. Endocrinology 141:3646–56.PubMedCrossRefGoogle Scholar
  18. Burdick D, Kosmoski J, Knauer MF, Glabe CG (1997). Preferential adsorption, internalization and resistance to degradation of the major isoform of the Alzheimer’s amyloid peptide, A beta 1–42, in differentiated PC 12 cells. Brain Res 746:275–284.PubMedCrossRefGoogle Scholar
  19. Calandra T, Bernhagen J, Metz CN, Splegel LA, Bacher M, Donnelly T, Cerami A, Bucala R (1995). MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377:68–71.PubMedCrossRefGoogle Scholar
  20. Castillo GM, Ngo C, Cummings J, Wight TN, Snow AD (1997). Perlecan binds to the β-amyloid proteins (Aβ) of Alzheimer’s disease, accelerates Aβ fibril formation, and maintains Aβ fibril stability. J Neurochem 69:2452–2465.PubMedCrossRefGoogle Scholar
  21. Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA (1995). Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: Evidence for early up-regulation of the endosomal-lysosomal system. Neuron 14:671–680.PubMedCrossRefGoogle Scholar
  22. Chao CC, Hu S, Peterson PK (1996). Glia: the not so innocent bystanders. J Neurovirol 2:234–239.PubMedCrossRefGoogle Scholar
  23. Chen K, Soriano F, Lyn W, Grajeda H, Masliah E, Games D (1998). Effects of entorhinal cortex lesions on hippocampal β-amyloid deposition in PDAPP transgenic mice. Society for Neuroscience 24 (#592.6):1502.Google Scholar
  24. Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RGM (2000). A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 408:975–979.PubMedCrossRefGoogle Scholar
  25. Christie RH, Chung H, Rebeck GW, Strickland D, Hyman BT (1996a). Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer’s disease. J Neuropathol Exp Neurol 55:491–498.PubMedCrossRefGoogle Scholar
  26. Christie RH, Freeman M, Hyman BT (1996b). Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer’s disease. Am J Pathol 148:399–403.PubMedGoogle Scholar
  27. Chu T, Tran T, Yang F, Beech W, Cole GM, Frautschy SA (1998). Effect of chloroquine and leupeptin on intracellular accumulation of amyloid-beta (Aβ) 1–42 peptide in a murine N9 microglial cell line. FEBS Lett 436:439–444.PubMedCrossRefGoogle Scholar
  28. Chung H, Brazil MI, Soe TT, Maxfield FR (1999). Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer’s amyloid beta-peptide by microglial cells. J Biol Chem 274:32301–32308.PubMedCrossRefGoogle Scholar
  29. Chung H, Wang R and Maxfield FR (2000). Degradation of β-amyloid peptide by microglia. Society for Neuroscience 26, 2286 (#858.10).Google Scholar
  30. Cole GM, Ard MD (2000). Influence of lipoproteins on microglial degradation of alzheimer’s amyloid beta—protein. Micros Res Tech 50:316–24.CrossRefGoogle Scholar
  31. Cole GM, Beech W, Frautschy SA, Sigel JJ, Glasgow C, Ard MD, (1999). Lipoprotein effects on Aβ accumulation and degradation by microglia in vitro. J Neuroscience Res 57:504–520.CrossRefGoogle Scholar
  32. Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT (1995). Estrogens, the immune response, and autoimmunity. Clin Exp Rheumatol 13:216–226.Google Scholar
  33. Dewitt DA, Perry G, Cohen M, Doller C, Silver J (1998). Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer’s disease. Exper Neurol 149:329–340.CrossRefGoogle Scholar
  34. Drew PD, Chavis JA (2000a). Female sex steroids: effects upon microglial cell activation. J Neuroimmunol 111:77–85.PubMedCrossRefGoogle Scholar
  35. Drew PD, Chavis JA (2000b). Inhibition of microglial cell activation by cortisol. Brain Res Bull 52:391–6PubMedCrossRefGoogle Scholar
  36. 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 382:716–719.PubMedCrossRefGoogle Scholar
  37. Fan JD, Wagner BL, McDonnell DP (1996). Identification of the sequences within the human complement 3 promoter required for estrogen responsiveness provides insight into the mechanism of tamoxifen mixed agonist activity. Mol Endocrinol 10:1605–1616.PubMedCrossRefGoogle Scholar
  38. Fox HS, Bond BL, Parsolow TG (1991). Estrogen regulates the IFN-gamma promoter. J Immunol 146:Google Scholar
  39. Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC (1992). Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce β-amyloid fibrils. Acta Neuropathol 84:225–233.PubMedCrossRefGoogle Scholar
  40. Frautschy SA, Albright T, Dvorak C, Wolfe DS, Baird A (1994). Transforming growth factor β (TGFβ) modification of β protein immunoreactivity in the hippocampus with and without β protein infusion and the resulting ultrastructural neuropathology. Neurobiol Aging 15(S1):S55–S56.CrossRefGoogle Scholar
  41. Frautschy SA, Cole GM, Baird A (1992). Phagocytosis and deposition of vascular β-amyloid in rat brains injected with Alzheimer β-amyloid. Am J Pathol 140:1389–1399.PubMedGoogle Scholar
  42. Frautschy SA, Yang F, Calderón L, Cole GM (1996). Rodent models of Alzheimer’s disease: rat Aβ infusion approaches to amyloid deposits. Neurobiol Aging 17:311–321.PubMedCrossRefGoogle Scholar
  43. Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM (1998). Microglial response to amyloid plaques in APPsw transgenic mice. Amer J Pathol 152:307–317.Google Scholar
  44. Games D, Khan KM, Soriano FG, Keim PS, Davis DL, Bryant K, Lieberburg I (1992). Lack of Alzheimer pathology after β-amyloid protein injections in rat brain. Neurobiol Aging 13:569–576.PubMedCrossRefGoogle Scholar
  45. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagoplan S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527.PubMedCrossRefGoogle Scholar
  46. Geddes JW, Anderson KJ, Cotman CW (1986). Senile plaques as aberrant sproutstimulating structures. Exp Neurol 94:767–776.PubMedCrossRefGoogle Scholar
  47. Gehrmann J, Banati RB (1995). Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J Neuropathol Exp Neurol 54:680–685.PubMedCrossRefGoogle Scholar
  48. Ghiso J, Matsubara E, Koudinov A, Choi-Miura NH, Tomita M, Wisniewski T, Frangione B (1993). The cerebrospinal-fluid soluble form of Alzheimer’s amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem J 293:27–30.PubMedGoogle Scholar
  49. Giulian D, Chen J, Ingeman JE, George JK, Noponen M (1989). The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J Neurosci 9:4416–4429.PubMedGoogle Scholar
  50. Gomez-Isla T, Wasco W, Pettingell WP, Gurubhagavatula S, Schmidt SD, Jondro PD, McNamara M, Rodes LA, DiBlasi T, Growdon WB, Seubert P, Schenk D, Growdon JH, Hyman BT, Tanzi RE (1997). A novel presenilin-1 mutation: increased β-amyloid and neurofibrillary changes. Ann Neurol 41:809–813.PubMedCrossRefGoogle Scholar
  51. Goodwin JL, Kehrli MEJr, Uemura E (1997). Integrin Mac-1 and β-amyloid in microglial release of nitric oxide. Brain Res 768:279–286.PubMedCrossRefGoogle Scholar
  52. Götz J, Chen F, van Dorpe J, Nitsch RM (2001). Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293:1491–1495.PubMedCrossRefGoogle Scholar
  53. Harris-White ME, Simmons M, Nash D, Miller SA, Chu T, Teter B, Cole GM, Frautschy SA (2001). Estrogen and glucocorticoid effects on microglia and Aβ clearance in vitro and in vivo. Neurochem Int 39:435–448.PubMedCrossRefGoogle Scholar
  54. Hartmann A, Veldhuis JD, Deuschle M, Standhardt H, Heuser I (1997). Twenty-four hour cortisol release profiles in patients with Alzheimer’s and Parkinson’s disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiol Aging 18:285–289.PubMedCrossRefGoogle Scholar
  55. Hayashi T, Yamada K, Esaki T, Muto E, Chaudhuri G, Iquchi Q (1998). Physiological concentrations of 17beta-estradiol inhibit the synthesis of nitric oxide synthase in macrophages via a receptor mediated system. J Cardiovascular Pharmacol 31:292–8.CrossRefGoogle Scholar
  56. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, et al., Duff K (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4:97–100.PubMedCrossRefGoogle Scholar
  57. Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D (1999). Behavioral changes in transgenic mice expressing both amyloi dprecursor protein and presenilin1 mutations: lack of association with amyloid deposits. Behav Genet 29:177–85.PubMedCrossRefGoogle Scholar
  58. Holtzman DM, Bales RK, Wu S, Bhat P, Parsadanian M, Fagan AM, Chang LK, Sun Y, Paul SM (1999). Expression of human apolipoprotein E reduces amyloid-B deposition in a mouse model of Alzheimer’s disease. J Clin Invest 103:R15—R21.PubMedCrossRefGoogle Scholar
  59. Holtzman DM, Pitas RE, Kilbridge J, Nathan B, Mahley RW, Bu G, Schwartz AL (1995). Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci USA 92:9480–9484.PubMedCrossRefGoogle Scholar
  60. Honda M, Akiyama H, Yamada Y, Kondo H, Kawabe Y, Takeya J, Takahashi K, Suzuki H, Doi T, Sakamoto A, et al. (1998). Immunohistochemical evidence for a macrophage scavenger receptor in Mato cells and reactive microglia of ischemia and Alzheimer’s disease. Biochem Biophys Res Commun 245:734–740.PubMedCrossRefGoogle Scholar
  61. Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S, Eckman C, Younkin S, Price D (1995). Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15:1203–1218.PubMedCrossRefGoogle Scholar
  62. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996). Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice. Science 274:99–102.PubMedCrossRefGoogle Scholar
  63. Huang F, Buttini M, Wyss-Coray T, McConlogue L, Kodama T, Pitas RE, Mucke L (1999). 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 155:1741–7.PubMedCrossRefGoogle Scholar
  64. Huang SS, Huang FW, Xu J, Chen S, Hsu CY, and Huang JS (1998). Amyloid beta-peptide possesses a transforming growth factor-beta activity. J Biol Chem 273:27640–27644.PubMedCrossRefGoogle Scholar
  65. Hyman BT, Strickland D, Rebeck GW (2000). Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease. Arch Neurol 57:646–650.PubMedCrossRefGoogle Scholar
  66. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT (1997a). APPsw Transgenic Mice develop age-related Aβ Deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol 56:965–973.PubMedCrossRefGoogle Scholar
  67. Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, Hyman BT (1997b). Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053–7059.PubMedGoogle Scholar
  68. Ishii K, Tamaoka A, Mizusawa H, Shoji S, Ohtake T, Fraser PE, Takahashi H, Tsuji S, Gearing M, Mizutani T, Yamada S, Kato M, St. George-Hyslop PH, Mina SS, Mori H (1997). Aβ 1–40 but not Aβ 1–42 levels in cortex correlate with apolipoprotein E E4 allele dosage in sporadic Alzheimer’s disease. Brain Res 748:250–252.PubMedCrossRefGoogle Scholar
  69. Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC (2000). Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: suppression lead to biochemical and pathological deposition. Nat Med 6:143–150.PubMedCrossRefGoogle Scholar
  70. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC (2001). Metabolic regulation of brain Abeta by neprilysin. Science 292: 1550–2.PubMedCrossRefGoogle Scholar
  71. Jantzen PT, Gordon MN, Connor KE, DiCarlo G, and Morgan DG (2000). Modification of microglial reactivity in MAPP/MPS 1 transgenic mice using NCX-2216 (nitroflurbiprofen). Society for Neuroscience 26(1061 (#397.14)).Google Scholar
  72. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HTJ, Nixon RA, Mercken M, Bergeron C, Fraser PE, St. George-Hysolop P, Westaway D (2000). Aβ peptide immunization reduces behavioral impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–982.PubMedCrossRefGoogle Scholar
  73. Jüttner S, Bernhagen J, Metz CNRM, Bucala R, Gessner A (1998). Migration inhibitory factor induces killing of leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-alpha. J Immunol 161:2383–90.PubMedGoogle Scholar
  74. Kaur C, Wu CH, Wen CY, Ling EA (1994). The effects of subcutaneous injections of glucocorticoids on amoeboid microglia in postnatal rats. Arch Histol Cytol 57:449–459.PubMedCrossRefGoogle Scholar
  75. Kopec KK, Carroll RT (2000). Phagocytosis is regulated by nitric oxide in murine microglia. Nitric Oxide 4:103–11.PubMedCrossRefGoogle Scholar
  76. Korotzer AR, Pike CJ, Cotman CW (1993). β-amyloid peptides induce degeneration of cultured rat microglia. Brain Res 624:121–125.Google Scholar
  77. Koudinov AR, Koudinova NV, Kumar A, Beavis RC, Ghiso J (1996). Biochemical characterization of Alzheimer’s soluble amyloid beta protein in human cerebrospinal fluid: Association with high density lipoproteins. Biochem Biophys Res Commun 223:592–597.PubMedCrossRefGoogle Scholar
  78. Kuo Y-M, Emmerling MR, Vigo-Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, Ball MJ, Roher AE (1996). Water-soluble Aβ (N-40,N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem 271:4077–4081.PubMedCrossRefGoogle Scholar
  79. LaDu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz GS (2000). Lipoproteins in the central nervous system. Ann N Y Acad Sci 903:167–175.PubMedCrossRefGoogle Scholar
  80. LaFerla FM, Troncoso JC, Strickland DK, Kawas CH, Jay G (1997). Neuronal cell death in Alzheimer’s disease correlates with ApoE uptake and intracellular Aβ stabilization. J Clin Invest 100:310–320.PubMedCrossRefGoogle Scholar
  81. Lewis J, Dickson DW, Lin W-L, Chisholm L, Corral A, Jones G, Yen S-H, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton J, McGowan E (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant Tau and APP. Science 293:1487–1491.PubMedCrossRefGoogle Scholar
  82. Li R, Shen Y, Yang LB, Lue LF, Finch C, Rogers J (2000). Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex. J Neurochem 75:1447–54.PubMedCrossRefGoogle Scholar
  83. Liao A, Nitsch RM, Greenberg SM, Finckh U, Blaccer D, Albert M, Rebeck GW, Gomez-Isla T, Clatworthy A, Binetti Geal (1998). Genetic association of an alpha22-macroglobulin (Va11100011e) polymorphism and Alzheimer’s disease. Hum Mol Genet 7:1953–6.PubMedCrossRefGoogle Scholar
  84. Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM (2000). Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 20(15):5709–14.PubMedGoogle Scholar
  85. Lorton D, Schaller J, Lala A, De Nardin E (2000). Chemotactic-like receptors and abeta peptide induced responses in Alzheimer’s disease. Neurobiol Aging 21:463–73.PubMedCrossRefGoogle Scholar
  86. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (1999). Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862.PubMedCrossRefGoogle Scholar
  87. Luedecking EK, DeKosky ST, Mehdi H, Ganguli M, Kamboh MI (2000). Analysis of genetic polymorphisms in the transforming growth factor-betal gene and the risk of Alzheimer’s disease. Hum Genet 106:565–9.PubMedCrossRefGoogle Scholar
  88. Mann DMA, Iwatsubo T, Pickering-Brown SM, Owen F, Saido TC, Perry RH (1997). Preferential deposition of amyloid β protein (Aβ) in the form of Aβ 40 in Alzheimer’s disease is associated with a gene dosage effect of the apolipoprotein E E4 allele. Neurosci Lett 221:81–84.PubMedCrossRefGoogle Scholar
  89. Marzolo MP, Von Bernhardi R, Bu G, Inestrosa NC, (2000) Expression of alpha2 macroglobulin receptor/low-density lipoprotein receptor-related protein (LRP) in rat microglial cells. J Neurosci Res 60:401–411.PubMedCrossRefGoogle Scholar
  90. McDonald DR, Bamberger ME, Combs CK, Landreth GE (1998). β-amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci 18:4451–60.Google Scholar
  91. McDonald DR, Brunden KR, Landreth GE (1997). Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci 17:2284–94.PubMedGoogle Scholar
  92. Meda L, Cassatella MA, Szendrei GI, Otvos L, Baron P, Villalba M, Ferrari D, Rossi F (1995). Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647–650.PubMedCrossRefGoogle Scholar
  93. Miller TP, Taylor J, Rogerson S, Mauricio M, Kennedy Q, Schatzberg A, Tinklenberg J, Yesavage J (1998). Cognitive and noncognitive symptoms in dementia patients: relationship to cortisol and dehydroepiandrosterone. Int Psychogeriats 10:85–96.CrossRefGoogle Scholar
  94. Moosmann B, Behl C (1999). The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent fom the estrogenic properties. Proc Nall Acad Sci USA 96:8867–72.CrossRefGoogle Scholar
  95. Morand EF, Leech M (1999). Glucocorticoid regulation of inflammation: the plot thickens. Inflamm Res 48:557–60.PubMedCrossRefGoogle Scholar
  96. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000). Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–985.PubMedCrossRefGoogle Scholar
  97. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD (2000). Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577.PubMedCrossRefGoogle Scholar
  98. Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilcock G, MacGowan S, Esiri MM, Murray LS, Dewar D, Love S, Moss T, Griffin WST (2000). Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Annals Neurol 47:365–368.CrossRefGoogle Scholar
  99. Oda T, Wals P, Osterburg HH, Johnson SA, Pasinetti G, Morgan TE, Rozovsky I, Blaine Stine W, Snyder SW, Holzman TF, Krafft GA, Finch CE, (1995) Clusterin (apoJ) alters the aggregation of amyloid β -peptide (Aβ 1–42) and forms slowly sedimenting Aβ complexes that cause oxidative stress. Exp Neurol 136:22–31.PubMedCrossRefGoogle Scholar
  100. Paresce DM, Chung HY, Maxfield FR (1997). Slow degradation of aggregates of the Alzheimer’s disease amyloid β-protein by microglial cells. J Biol Chem 272:29390–29397.PubMedCrossRefGoogle Scholar
  101. Paresce DM, Ghosh RN, Maxfield FR (1996). Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor. Neuron 17:553–565.PubMedCrossRefGoogle Scholar
  102. Pike CJ, Ramezan-Arab N, Cotman CW (1997). Beta-amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants. J Neurochem 69:1601–1611.PubMedCrossRefGoogle Scholar
  103. Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991). In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 563:311–314.PubMedCrossRefGoogle Scholar
  104. Pow DV, Perry VH, Morris JF, Gordon S (1989). Microglia in the neurohypophysis associate with and endocytose terminal portions of neurosecretory neurons. Neuroscience 33:567–578.PubMedCrossRefGoogle Scholar
  105. Probst A, Langui D, Ipsen S, Robakis N, Ulrich J (1991). Deposition of β/A4 protein along neuronal plasma membranes in diffuse senile plaques. Acta Neuropathol 83:21–29.PubMedCrossRefGoogle Scholar
  106. Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993). Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11:575–580.PubMedCrossRefGoogle Scholar
  107. Ritter M, Buechler C, Langmann T, Orso E, Klucken J, Schmitz G (1999). The scavenger receptor CD 163: regulation, promoter structure and genomic organization. Pathobiology 67:257–61.PubMedCrossRefGoogle Scholar
  108. Sadeghi R, Hawrylowicz CM, Chernajovsky Y, Feldmann M (1992). Synergism of glucocorticoids with granulocyte macrophage colony stimulating factor (GM-CSF) but not inteferon gamma (IFN-gamma) or interleukin-4 (IL-4) on induction of HLA class II expression on human monocytes. Cytokine 4:287–97.PubMedCrossRefGoogle Scholar
  109. Savage MJ, Trusko SP, Howland DS, Pinsker LR, Mistretta S, Reaume AG, Greenberg BD, Siman R, Scott RW (1998). Turnover of amyloid β-protein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci 18:1743–1752.PubMedGoogle Scholar
  110. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999). Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177.PubMedCrossRefGoogle Scholar
  111. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Selkoe D, Younkin S (1996). Secreted amyloid β -protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2:864–870.PubMedCrossRefGoogle Scholar
  112. Shaffer LM, Dority MD, Gupta-Bansal R, Frederickson RC, Younkin SG, Brunden KR (1995). Amyloid beta protein removal by neuroglial cells in culture. Neurobiol Aging 16:737–745.PubMedCrossRefGoogle Scholar
  113. Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, and Jucker M (1999). Association of microglia with amyloid plaques in brains of APP23 transgenic mice [see comments]. Am J Pathol 154(6), 1673–84.PubMedCrossRefGoogle Scholar
  114. Stewart WF, Kawas C, Corrada M, Metter EJ (1997). Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48:626–631.PubMedCrossRefGoogle Scholar
  115. Stone DJ, Rozovsky I, Morgan TE, Anderson CP, Hajian H, Finch CE (1997). Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro. Exp Neurol 143:313–318.PubMedCrossRefGoogle Scholar
  116. Strickland RW, Wahl LH, Finbloom DS (1986). Corticosteroids enhance the binding of recombinant interferon to cultured human monocytes. J Immunol 137:Google Scholar
  117. Swanwick GR, Kirby M, Bruce I, Buggy F, Coen RF, Coakley D, Lawlor BA (1998). Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer’s disease: lack of association between longitudinal and cross-sectional findings. Am J Psychiatry 155:286–289.PubMedGoogle Scholar
  118. Tanaka J, Fujita H, Matsuda S, Toku K, Sakanaka M, Maeda N (1997). Glucocorticoid- and mineralocorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids. Glia 20:23–37.PubMedCrossRefGoogle Scholar
  119. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991). Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive imparirment. Ann Neurol 30:572–580.PubMedCrossRefGoogle Scholar
  120. Thome J, Baumer A, Kornhuber J, Rosler M, Riederer P (1995). Alpha- l -antichymotrypsin bi-allele polymorphism apolipoprotein-E tri-allele polymorphism and genetic risk of Alzheimer syndrome. J Neural Transm 10:207–212.CrossRefGoogle Scholar
  121. Torp R, Head E, Milgram NW, Hahn F, Ottersen OP, Cotman CW (2000). Ultrastructural evidence of fibrillar beta-amyloid associated with neuronal membranes in behaviorally characterized aged dog brains. Neuroscience 96:495–506.PubMedCrossRefGoogle Scholar
  122. Vekrellis K, Chiu S, Mansourian S, Selkoe D (2000a). Insulin-degrading enzyme is the major Aβ-degrading protease in human control and Alzheimer’s disease brains. Society for Neuroscience 26:1573 (#588.5).Google Scholar
  123. Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ (2000b). Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme. J Neurosci 20:1657–1665.PubMedGoogle Scholar
  124. Wang HY, Lee DH, Davis CB, and Shank RP (2000). Amyloid peptide abeta(1–42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem 75(3), 1155–61.PubMedCrossRefGoogle Scholar
  125. Weiner MF, Vobach S, Svetlik D, Risser RC (1993). Cortisol secretion and Alzheimer’s disease progression: a preliminary report. Biol Psychiatry 34:158–161.PubMedCrossRefGoogle Scholar
  126. Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O’Hare E, Esler WP, Maggio JE, Mantyh PW (1998). Fibrillar β-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci 18:2161–2173.PubMedGoogle Scholar
  127. Whitson JS, Selkoe DJ, Cotman CW (1989). Amyloid β protein enhances the survival of hippocampal neurons in vitro. Science 243:1488–1490.PubMedCrossRefGoogle Scholar
  128. Winkler J, Connor DJ, Frautschy SA, Behl C, Waite JJ, Cole GM, Thal LJ (1994). Lack of long-term effects after β-Amyloid protein injections in rat brain. Neurobiol Aging 15:601.PubMedCrossRefGoogle Scholar
  129. Wisniewski HM, Barcikowska M, Kida E (1991). Phagocytosis of β/A4 amyloid fibrils of the neuritic neocortical plaques. Acta Neuropathol 81:588–590.PubMedCrossRefGoogle Scholar
  130. Wisniewski HM, Weigel J, Wang KC, Kujawa M, Lach B (1989). Ultrastructural studies of the cells forming amyloid fibers in classical plaques. Can J Neurol Sci 16:535–542.PubMedGoogle Scholar
  131. Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, Mucke L (1997). Amyloidogenic role of cytokine TGF-beta-1 in transgenic mice and in Alzheimer’s disease. Nature 389:603–605.PubMedCrossRefGoogle Scholar
  132. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L (2001). TGF beta 1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7:612–8.PubMedCrossRefGoogle Scholar
  133. Yamada Y, Doi T, Hamakubo T, Kodama T (1998). Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system. Cell Mol Life Sci 54:628–640.PubMedCrossRefGoogle Scholar
  134. 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 [see comments]. Nature 382:685–91.PubMedCrossRefGoogle Scholar
  135. Yan SD, Roher A, Chaney M, Zlokovic B, Schmidt AM, Stern D (2000). Cellular cofactors potentiating induction of stress and the cytotoxicity by amyloid beta-peptide. Biochim Biophys Acta 1502:145–157.PubMedCrossRefGoogle Scholar
  136. Yan SD, Zhu H, Fu J, Yan SF, Roher A, Tourtellotte WW, Rajavashisth T, Chen X, Godman GC, Stern D, Schmidt AM (1997). Amyloid-β peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer’s disease. Proc Natl Acad Sci USA 94:5296–5301.PubMedCrossRefGoogle Scholar
  137. Yang AJ, Chandswangbhuvana D, Margol L, Glabe CG (1998). Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Aβ1–42 pathogenesis. J Neurosci 52:691–8.CrossRefGoogle Scholar
  138. Yang AJ, Knauer M, Burdick DA, Glabe C (1995). Intracellular Aβ1–42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells. J Biol Chem 270:14786–14792.PubMedCrossRefGoogle Scholar
  139. Yankner BA, Duffy LK, Kirschner DA (1990). Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282.PubMedCrossRefGoogle Scholar
  140. Younkin SG (1995). Evidence that Aβ42 is the real culprit in Alzheimer’s disease. Ann Neurol 37:287–288.PubMedCrossRefGoogle Scholar
  141. Zlokovic BV, Martel CL, Mackic JB, Matsubara E, Wisniewski T, McComb JG, Frangione B, Ghiso J (1994). Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer’s amyloid beta. Biochem Biophys Res Commun 205:1431–1437.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Sally A. Frautschy
  • Greg M. Cole
  • March D. Ard

There are no affiliations available

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