Immunology and immunotherapy of Alzheimer's disease (original) (raw)

• Braak, H., Braak, E. & Bohl, J. Staging of Alzheimer-related cortical destruction. Eur. Neurol. 33, 403–408 (1993).
  Article CAS PubMed Google Scholar
• Jellinger, K. A. & Bancher, C. AD neuropathology. Neurology 46, 1186–1187 (1996).
  Article CAS PubMed Google Scholar
• Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
  Article CAS PubMed Google Scholar
• Selkoe, D. J. Alzheimer's disease: a central role for amyloid. J. Neuropathol. Exp. Neurol. 53, 438–447 (1994). This article explains the amyloid hypothesis in Alzheimer's disease.
  Article CAS PubMed Google Scholar
• Gouras, G. K., Almeida, C. G. & Takahashi, R. H. Intraneuronal Aβ accumulation and origin of plaques in Alzheimer's disease. Neurobiol. Aging 26, 1235–1244 (2005).
  Article CAS PubMed Google Scholar
• Turner, P. R., O'Connor, K., Tate, W. P. & Abraham, W. C. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog. Neurobiol. 70, 1–32 (2003).
  Article CAS PubMed Google Scholar
• Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).
  Article CAS PubMed Google Scholar
• Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996). This article shows a correlation between amyloid-β load and cognitive memory deficits in APP -transgenic mice.
  Article CAS PubMed Google Scholar
• Routtenberg, A. Measuring memory in a mouse model of Alzheimer's disease. Science 277, 839–841 (1997).
  Article CAS PubMed Google Scholar
• Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287–13292 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Bronfman, F. C., Moechars, D. & Van Leuven, F. Acetylcholinesterase-positive fiber deafferentation and cell shrinkage in the septohippocampal pathway of aged amyloid precursor protein London mutant transgenic mice. Neurobiol. Dis. 7, 152–168 (2000).
  Article CAS PubMed Google Scholar
• Dewachter, I. et al. Modeling Alzheimer's disease in transgenic mice: effect of age and of presenilin1 on amyloid biochemistry and pathology in APP/London mice. Exp. Gerontol. 35, 831–841 (2000).
  Article CAS PubMed Google Scholar
• Kuo, Y. M. et al. Comparative analysis of amyloid-β chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J. Biol. Chem. 276, 12991–12998 (2001).
  Article CAS PubMed Google Scholar
• Morgan, D. et al. Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982–985 (2000).
  Article CAS PubMed Google Scholar
• Janus, C. et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979–982 (2000).
  Article CAS PubMed Google Scholar
• McGeer, P. L. & McGeer, E. G. Inflammation, autotoxicity and Alzheimer disease. Neurobiol. Aging 22, 799–809 (2001). This article describes the innate immune response in Alzheimer's disease.
  Article CAS PubMed Google Scholar
• Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Togo, T. et al. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J. Neuroimmunol. 124, 83–92 (2002).
  Article CAS PubMed Google Scholar
• McGeer, E. G. & McGeer, P. L. Innate immunity in Alzheimer's disease: a model for local inflammatory reactions. Mol. Interv. 1, 22–29 (2001). References 18 and 19 show that lowering amyloid-β by anti-amyloid therapy improves cognitive behaviour in APP -transgenic mice.
  CAS PubMed Google Scholar
• Rogers, J. et al. Complement activation by β-amyloid in Alzheimer disease. Proc. Natl Acad. Sci. USA 89, 10016–10020 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Webster, S. & Rogers, J. Relative efficacies of amyloid β peptide (Aβ) binding proteins in Aβ aggregation. J. Neurosci. Res. 46, 58–66 (1996).
  Article CAS PubMed Google Scholar
• McGreal, E. & Gasque, P. Structure-function studies of the receptors for complement C1q. Biochem. Soc. Trans. 30, 1010–1014 (2002).
  Article CAS PubMed Google Scholar
• Hafer-Macko, C. E., Dyck, P. J. & Koski, C. L. Complement activation in acquired and hereditary amyloid neuropathy. J. Peripher. Nerv. Syst. 5, 131–139 (2000).
  Article CAS PubMed Google Scholar
• Webster, S. D. et al. Antibody-mediated phagocytosis of the amyloid β-peptide in microglia is differentially modulated by C1q. J. Immunol. 166, 7496–7503 (2001).
  Article CAS PubMed Google Scholar
• El Khoury, J. et al. Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 382, 716–719 (1996). A description of the importance of scavenger receptors on microglial cells for amyloid uptake.
  Article CAS PubMed Google Scholar
• Minghetti, L. Role of inflammation in neurodegenerative diseases. Curr. Opin. Neurol. 18, 315–321 (2005).
  Article CAS PubMed Google Scholar
• Bianca, V. D., Dusi, S., Bianchini, E., Dal Pra, I. & Rossi, F. β-amyloid activates the O2 forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease. J. Biol. Chem. 274, 15493–15499 (1999).
  Article CAS PubMed Google Scholar
• Weldon, D. T. et al. 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 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• McGeer, E. G. & McGeer, P. L. The importance of inflammatory mechanisms in Alzheimer disease. Exp. Gerontol. 33, 371–378 (1998).
  Article CAS PubMed Google Scholar
• Van Muiswinkel, F. L. et al. The amino-terminus of the amyloid-β protein is critical for the cellular binding and consequent activation of the respiratory burst of human macrophages. J. Neuroimmunol. 96, 121–130 (1999).
  Article CAS PubMed Google Scholar
• Ishii, K. et al. Subacute NO generation induced by Alzheimer's β-amyloid in the living brain: reversal by inhibition of the inducible NO synthase. FASEB J. 14, 1485–1489 (2000).
  CAS PubMed Google Scholar
• Heneka, M. T. et al. Induction of nitric oxide synthase and nitric oxide-mediated apoptosis in neuronal PC12 cells after stimulation with tumour necrosis factor-α/lipopolysaccharide. J. Neurochem. 71, 88–94 (1998).
  Article CAS PubMed Google Scholar
• Combs, C. K., Karlo, J. C., Kao, S. C. & Landreth, G. E. β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179–1188 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Butovsky, O., Talpalar, A. E., Ben-Yaakov, K. & Schwartz, M. Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protective. Mol. Cell. Neurosci. 29, 381–393 (2005).
  Article CAS PubMed Google Scholar
• Streit, W. J. Microglia and Alzheimer's disease pathogenesis. J. Neurosci. Res. 77, 1–8 (2004).
  Article CAS PubMed Google Scholar
• Nicoll, J. A. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nature Med. 9, 448–452 (2003). A case report of neuropathology in a patient who developed meningoencephalitis following immunization with amyloid-β peptide.
  Article CAS PubMed Google Scholar
• Akiyama, H. & McGeer, P. L. Specificity of mechanisms for plaque removal after Aβ immunotherapy for Alzheimer disease. Nature Med. 10, 117–119 (2004).
  Article CAS PubMed Google Scholar
• Weiner, H. L. & Selkoe, D. J. Inflammation and therapeutic vaccination in CNS diseases. Nature 420, 879–884 (2002).
  Article CAS PubMed Google Scholar
• Monsonego, A. & Weiner, H. L. Immunotherapeutic approaches to Alzheimer's disease. Science 302, 834–838 (2003).
  Article CAS PubMed Google Scholar
• Meda, L., Baron, P. & Scarlato, G. Glial activation in Alzheimer's disease: the role of Aβ and its associated proteins. Neurobiol. Aging 22, 885–893 (2001).
  Article CAS PubMed Google Scholar
• Bamberger, M. E. & Landreth, G. E. Microglial interaction with β-amyloid: implications for the pathogenesis of Alzheimer's disease. Microsc. Res. Tech. 54, 59–70 (2001).
  Article CAS PubMed Google Scholar
• Kitazawa, M., Yamasaki, T. R. & Laferla, F. M. Microglia as a potential bridge between the amyloid β-peptide and Tau. Ann. N.Y. Acad. Sci. 1035, 85–103 (2004).
  Article CAS PubMed Google Scholar
• DeWitt, D. A., Perry, G., Cohen, M., Doller, C. & Silver, J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Exp. Neurol. 149, 329–340 (1998).
  Article CAS PubMed Google Scholar
• Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nature Med. 9, 453–457 (2003).
  Article CAS PubMed Google Scholar
• Koistinaho, M. et al. Apolipoprotein E promotes astrocyte co-localization and degradation of deposited amyloid-β peptides. Nature Med. 10, 719–726 (2004).
  Article CAS PubMed Google Scholar
• Dolev, I. & Michaelson, D. M. A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade. Proc. Natl Acad. Sci. USA 101, 13909–13914 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• McGeer, P. L., Schulzer, M. & McGeer, E. G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47, 425–432 (1996).
  Article CAS PubMed Google Scholar
• Myriad. Molecule of the month. MPC-7869 (Flurizan). Drug News Perspect. 18, 141 (2005).
• Yasojima, K., Schwab, C., McGeer, E. G. & McGeer, P. L. Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res. 830, 226–236 (1999).
  Article CAS PubMed Google Scholar
• Xiang, Z. et al. Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr. 10, 271–278 (2002).
  Article CAS PubMed Google Scholar
• Nogawa, S., Zhang, F., Ross, M. E. & Iadecola, C. Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J. Neurosci. 17, 2746–2755 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Hoozemans, J. J., Veerhuis, R., Rozemuller, A. J. & Eikelenboom, P. Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease. Curr. Drug Targets 4, 461–468 (2003).
  Article CAS PubMed Google Scholar
• Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212–216 (2001). A description of lowering of amyloid load in APP -transgenic mice by NSAIDs that is independent of their anti-inflammatory activity.
  Article CAS PubMed Google Scholar
• Takahashi, Y. et al. Sulindac sulfide is a noncompetitive γ-secretase inhibitor that preferentially reduces Aβ42 generation. J. Biol. Chem. 278, 18664–18670 (2003).
  Article CAS PubMed Google Scholar
• Reid, G. et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc. Natl Acad. Sci. USA 100, 9244–9249 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Warner, T. D. & Mitchell, J. A. Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: as easy as ABC? Proc. Natl Acad. Sci. USA 100, 9108–9110 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Xu, H., Sweeney, D., Greengard, P. & Gandy, S. Metabolism of Alzheimer β-amyloid precursor protein: regulation by protein kinase A in intact cells and in a cell-free system. Proc. Natl Acad. Sci. USA 93, 4081–4084 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Marambaud, P., Ancolio, K., Lopez-Perez, E. & Checler, F. Proteasome inhibitors prevent the degradation of familial Alzheimer's disease-linked presenilin 1 and potentiate Aβ42 recovery from human cells. Mol. Med. 4, 147–157 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Aisen, P. S. et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 2819–2826 (2003).
  Article CAS PubMed Google Scholar
• Jantzen, P. T. et al. Microglial activation and β-amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J. Neurosci. 22, 2246–2254 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Solomon, B., Koppel, R., Hanan, E. & Katzav, T. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer β-amyloid peptide. Proc. Natl Acad. Sci. USA 93, 452–455 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Solomon, B., Koppel, R., Frenkel, D. & Hanan-Aharon, E. Disaggregation of Alzheimer β-amyloid by site-directed mAb. Proc. Natl Acad. Sci. USA 94, 4109–4112 (1997). A demonstration that antibody can reduce amyloid-β fibril formation in vitro.
  Article CAS PubMed PubMed Central Google Scholar
• Frenkel, D., Balass, M. & Solomon, B. N-terminal EFRH sequence of Alzheimer's β-amyloid peptide represents the epitope of its anti-aggregating antibodies. J. Neuroimmunol. 88, 85–90 (1998).
  Article CAS PubMed Google Scholar
• Frenkel, D., Balass, M., Katchalski-Katzir, E. & Solomon, B. High affinity binding of monoclonal antibodies to the sequential epitope EFRH of β-amyloid peptide is essential for modulation of fibrillar aggregation. J. Neuroimmunol. 95, 136–142 (1999).
  Article CAS PubMed Google Scholar
• Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999). A demonstration that immunization of APP -transgenic mice with amyloid-β clears amyloid.
  Article CAS PubMed Google Scholar
• Weiner, H. L. et al. Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann. Neurol. 48, 567–579 (2000). Mucosal amyloid immunization reduces amyloid plaques in vivo.
  Article CAS PubMed Google Scholar
• Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000). Passive administration of amyloid-β-specific antibody can clear amyloid plaques in vivo.
  Article CAS PubMed Google Scholar
• Dodart, J. C. et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nature Neurosci. 5, 452–457 (2002).
  Article CAS PubMed Google Scholar
• DeMattos, R. B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 8850–8855 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Sigurdsson, E. M., Scholtzova, H., Mehta, P. D., Frangione, B. & Wisniewski, T. Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am. J. Pathol. 159, 439–447 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Vehmas, A. K. et al. β-amyloid peptide vaccination results in marked changes in serum and brain Aβ levels in APPswe/PS1ΔE9 mice, as detected by SELDI-TOF-based ProteinChip technology. DNA Cell Biol. 20, 713–721 (2001).
  Article CAS PubMed Google Scholar
• Li, Q. et al. Overcoming antigen masking of anti-amyloid-β antibodies reveals breaking of B cell tolerance by virus-like particles in amyloid-β immunized amyloid precursor protein transgenic mice. BMC Neurosci. 5, 21 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Das, P. et al. Amyloid-β immunization effectively reduces amyloid deposition in FcRγ−/− knock-out mice. J. Neurosci. 23, 8532–8538 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, J. et al. A novel recombinant adeno-associated virus vaccine reduces behavioural impairment and β-amyloid plaques in a mouse model of Alzheimer's disease. Neurobiol. Dis. 14, 365–379 (2003).
  Article CAS PubMed Google Scholar
• Lemere C. A. et al. Evidence for peripheral clearance of cerebral Aβ protein following chronic, active Aβ immunization in PSAPP mice. Neurobiol. Dis. 14, 10–18 (2003).
  Article CAS PubMed Google Scholar
• Schiltz, J. G. et al. Antibodies from a DNA peptide vaccination decrease the brain amyloid burden in a mouse model of Alzheimer's disease. J. Mol. Med. 82, 706–714 (2004).
  Article PubMed CAS Google Scholar
• Hara, H. et al. Development of a safe oral Aβ vaccine using recombinant adeno-associated virus vector for Alzheimer's disease. J. Alzheimers Dis. 6, 483–488 (2004).
  Article CAS PubMed Google Scholar
• Frenkel, D., Katz, O. & Solomon, B. Immunization against Alzheimer's β-amyloid plaques via EFRH phage administration. Proc. Natl Acad. Sci. USA 97, 11455–11459 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Frenkel, D., Dewachter, I., Van Leuven, F. & Solomon, B. Reduction of β-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization. Vaccine 21, 1060–1065 (2003).
  Article CAS PubMed Google Scholar
• Lavie, V. et al. EFRH-phage immunization of Alzheimer's disease animal model improves behavioural performance in Morris water maze trials. J. Mol. Neurosci. 24, 105–113 (2004).
  Article CAS PubMed Google Scholar
• Lee, E. B. et al. Targeting Aβ oligomers by passive immunization with a conformation selective monoclonal antibody improves learning and memory in APP transgenic mice. J. Biol. Chem. 281, 4292–4299 (2005).
  Article PubMed CAS Google Scholar
• Levites, Y. et al. Anti-Aβ42- and anti-Aβ40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J. Clin. Invest. 116, 193–201 (2006).
  Article CAS PubMed Google Scholar
• McLaurin, J. et al. Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nature Med. 8, 1263–1269 (2002).
  Article CAS PubMed Google Scholar
• Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 (2004).
  Article CAS PubMed Google Scholar
• Morgan, D. & Gitter, B. D. Evidence supporting a role for anti-Aβ antibodies in the treatment of Alzheimer's disease. Neurobiol. Aging 25, 605–608 (2004).
  Article CAS PubMed Google Scholar
• Klyubin, I. et al. Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nature Med. 11, 556–561 (2005).
  Article CAS PubMed Google Scholar
• Wilcock, D. M. et al. Microglial activation facilitates Aβ plaque removal following intracranial anti-Aβ antibody administration. Neurobiol. Dis. 15, 11–20 (2004).
  Article CAS PubMed Google Scholar
• Gilman, S. et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64, 1553–1562 (2005). Clinical and pathological effects following amyloid-β immunization of humans are described.
  Article CAS PubMed Google Scholar
• Bayer, A. J. et al. Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD. Neurology 64, 94–101 (2005).
  Article CAS PubMed Google Scholar
• Orgogozo, J. M. et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology 61, 46–54 (2003).
  Article CAS PubMed Google Scholar
• Hock, C. et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease. Neuron 38, 547–554 (2003). Cognitive improvement in patients with Alzheimer's disease with high amyloid-β-specific antibody titres following amyloid-β immunization.
  Article CAS PubMed Google Scholar
• Fox, N. C. et al. Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 64, 1563–1572 (2005).
  Article CAS PubMed Google Scholar
• Ferrer, I., Boada Rovira, M., Sanchez Guerra, M. L., Rey, M. J. & Costa-Jussa, F. Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease. Brain Pathol. 14, 11–20 (2004).
  Article CAS PubMed Google Scholar
• Masliah, E. et al. Aβ vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64, 129–131 (2005).
  Article CAS PubMed Google Scholar
• Monsonego, A. et al. Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease. J. Clin. Invest. 112, 415–422 (2003). Elderly subjects and Alzheimer's disease patients have increased T-cell responses to amyloid-β in peripheral blood.
  Article CAS PubMed PubMed Central Google Scholar
• O'Toole, M. et al. Risk factors associated with β-amyloid1–42 immunotherapy in preimmunization gene expression patterns of blood cells. Arch. Neurol. 62, 1531–1536 (2005).
  Article PubMed Google Scholar
• Schenk, D., Hagen, M. & Seubert, P. Current progress in β-amyloid immunotherapy. Curr. Opin. Immunol. 16, 599–606 (2004).
  Article CAS PubMed Google Scholar
• Pfeifer, M. et al. Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 298, 1379 (2002).
  Article CAS PubMed Google Scholar
• DiCarlo, G., Wilcock, D., Henderson, D., Gordon, M. & Morgan, D. Intrahippocampal LPS injections reduce Aβ load in APP+PS1 transgenic mice. Neurobiol. Aging 22, 1007–1012 (2001).
  Article CAS PubMed Google Scholar
• Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl Acad. Sci. USA 99, 10837–10842 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Wilcock, D. M. et al. Intracranially administered anti-Aβ antibodies reduce β-amyloid deposition by mechanisms both independent of and associated with microglial activation. J. Neurosci. 23, 3745–37451 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Frenkel, D., Maron, R., Burt, D. S. & Weiner, H. L. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease. J. Clin. Invest. 115, 2423–2433 (2005). Antibody-independent reduction of amyloid in APP -transgenic mice following microglial-cell activation by myelin antigens and glatiramer acetate.
  Article CAS PubMed PubMed Central Google Scholar
• Nakagawa, Y. et al. Brain trauma in aged transgenic mice induces regression of established Aβ deposits. Exp. Neurol. 163, 244–252 (2000).
  Article CAS PubMed Google Scholar
• Wyss-Coray, T. et al. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nature Med. 7, 612–618 (2001).
  Article CAS PubMed Google Scholar
• Rogers, J., Strohmeyer, R., Kovelowski, C. J. & Li, R. Microglia and inflammatory mechanisms in the clearance of amyloid β peptide. Glia 40, 260–269 (2002).
  Article PubMed Google Scholar
• Bacskai, B. J. et al. Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nature Med. 7, 369–372 (2001).
  Article CAS PubMed Google Scholar
• Mitrasinovic, O. M. & Murphy, G. M. Jr. Microglial overexpression of the M-CSF receptor augments phagocytosis of opsonized Aβ. Neurobiol. Aging 24, 807–815 (2003).
  Article CAS PubMed Google Scholar
• Bacskai, B. J. et al. Non-Fc-mediated mechanisms are involved in clearance of amyloid-β in vivo by immunotherapy. J. Neurosci. 22, 7873–7878 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Frenkel, D., Solomon, B. & Benhar, I. Modulation of Alzheimer's β-amyloid neurotoxicity by site-directed single-chain antibody. J. Neuroimmunol. 106, 23–31 (2000).
  Article CAS PubMed Google Scholar
• Thomas, C. J. et al. Evidence of a trimolecular complex involving LPS, LPS binding protein and soluble CD14 as an effector of LPS response. FEBS Lett. 531, 184–188 (2002).
  Article CAS PubMed Google Scholar
• Hauss-Wegrzyniak, B., Vraniak, P. D. & Wenk, G. L. LPS-induced neuroinflammatory effects do not recover with time. Neuroreport 11, 1759–1763 (2000).
  Article CAS PubMed Google Scholar
• Stalder, A. K. et al. Lipopolysaccharide-induced IL-12 expression in the central nervous system and cultured astrocytes and microglia. J. Immunol. 159, 1344–1351 (1997).
  CAS PubMed Google Scholar
• Sly, L. M. et al. Endogenous brain cytokine mRNA and inflammatory responses to lipopolysaccharide are elevated in the Tg2576 transgenic mouse model of Alzheimer's disease. Brain Res. Bull. 56, 581–588 (2001).
  Article CAS PubMed Google Scholar
• Qiao, X., Cummins, D. J. & Paul, S. M. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur. J. Neurosci. 14, 474–482 (2001).
  Article CAS PubMed Google Scholar
• Sheng, J. G. et al. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid β peptide in APPswe transgenic mice. Neurobiol. Dis. 14, 133–145 (2003).
  Article CAS PubMed Google Scholar
• Herber, D. L. et al. Time-dependent reduction in Aβ levels after intracranial LPS administration in APP transgenic mice. Exp. Neurol. 190, 245–253 (2004).
  Article CAS PubMed Google Scholar
• Quinn, J. et al. Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease. J. Neuroimmunol. 137, 32–41 (2003).
  Article CAS PubMed Google Scholar
• Jones, T. et al. Protollin: a novel adjuvant for intranasal vaccines. Vaccine 22, 3691–3697 (2004).
  Article CAS PubMed Google Scholar
• Coraci, I. S. et al. 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 β-amyloid fibrils. Am. J. Pathol. 160, 101–112 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J. & Landreth, G. E. A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J. Neurosci. 23, 2665–2674 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Porter, J. C. & Hogg, N. Integrins take partners: cross-talk between integrins and other membrane receptors. Trends Cell Biol. 8, 390–396 (1998).
  Article CAS PubMed Google Scholar
• Paresce, D. M., Ghosh, R. N. & Maxfield, F. R. Microglial cells internalize aggregates of the Alzheimer's disease amyloid β-protein via a scavenger receptor. Neuron 17, 553–565 (1996).
  Article CAS PubMed Google Scholar
• Iribarren, P. et al. CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid β1–42 peptide by upregulating the expression of the G-protein-coupled receptor mFPR2. FASEB J. 19, 2032–2034 (2005).
  Article CAS PubMed Google Scholar
• Iribarren, P., Zhou, Y., Hu, J., Le, Y. & Wang, J. M. Role of formyl peptide receptor-like 1 (FPRL1/FPR2) in mononuclear phagocyte responses in Alzheimer disease. Immunol. Res. 31, 165–176 (2005).
  Article CAS PubMed Google Scholar
• Verdier, Y., Zarandi, M. & Penke, B. Amyloid β-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. J. Pept. Sci. 10, 229–248 (2004).
  Article CAS PubMed Google Scholar
• Giulian, D. et al. The HHQK domain of β-amyloid provides a structural basis for the immunopathology of Alzheimer's disease. J. Biol. Chem. 273, 29719–29726 (1998).
  Article CAS PubMed Google Scholar
• Xie, L. et al. Alzheimer's β-amyloid peptides compete for insulin binding to the insulin receptor. J. Neurosci. 22, RC221 (2002).
  Article PubMed PubMed Central Google Scholar
• Boland, K., Behrens, M., Choi, D., Manias, K. & Perlmutter, D. H. The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-β peptide but not aggregated, cytotoxic amyloid-β peptide. J. Biol. Chem. 271, 18032–18044 (1996).
  Article CAS PubMed Google Scholar
• Qiu, W. Q. et al. Insulin-degrading enzyme regulates extracellular levels of amyloid β-protein by degradation. J. Biol. Chem. 273, 32730–32738 (1998).
  Article CAS PubMed Google Scholar
• Yamada, T. et al. Selective localization of gelatinase A, an enzyme degrading β-amyloid protein, in white matter microglia and in Schwann cells. Acta Neuropathol. (Berl) 89, 199–203 (1995).
  Article CAS Google Scholar
• Simard, A. R., Soulet, D., Gowing, G., Julien, J. P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489–502 (2006).
  Article CAS PubMed Google Scholar
• Schwartz, M., Butovsky, O., Bruck, W. & Hanisch, U. K. Microglial phenotype: is the commitment reversible? Trends Neurosci. 29, 68–74 (2006). A description of the role of different microglial-cell subsets in the CNS.
  Article CAS PubMed Google Scholar
• Monsonego, A., Maron, R., Zota, V., Selkoe, D. J. & Weiner, H. L. Immune hyporesponsiveness to amyloid β-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 10273–10278 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Furlan, R. et al. Vaccination with amyloid-β peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain 126, 285–291 (2003).
  Article PubMed Google Scholar
• Monsonego, A. et al. Aβ-induced meningoencephalitis is IFN-γ dependent and is associated with T-cell dependent clearance of Aβ in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 103, 5048–5053 (2006). Description of meningoencephalitis in APP -transgenic mice and reduction of amyloid-β levels mediated by amyloid-β-specific T cells.
  Article CAS PubMed PubMed Central Google Scholar
• Weiner, H. L. et al. Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann. Neurol. 48, 567–579 (2000).
  Article CAS PubMed Google Scholar
• Tan, J. et al. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nature Neurosci. 5, 1288–1293 (2002).
  Article CAS PubMed Google Scholar
• LaFerla, F. M. & Oddo, S. Alzheimer's disease: Aβ, tau and synaptic dysfunction. Trends Mol. Med. 11, 170–176 (2005).
  Article CAS PubMed Google Scholar
• Yamamoto, M. et al. Overexpression of monocyte chemotactic protein-1/CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition. Am. J. Pathol. 166, 1475–1485 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Fonseca, M. I., Zhou, J., Botto, M. & Tenner, A. J. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J. Neurosci. 24, 6457–6465 (2004).
  Article CAS PubMed PubMed Central Google Scholar