Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease
Abstract
One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.
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Anti-apoE antibody might modulate similar inflammatory responses, consistent with the effect of certain anti-Aβ antibodies.
“This finding suggests that anti-apoE antibody might modulate similar inflammatory responses, which is consistent with the effect of certain anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2004).”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as Bard et al., 2000
Recruitment and activation of microglia around plaques and subsequent Aβ degradation/clearance have been proposed as one of the mechanisms by which Aβ immunotherapy decreases amyloid levels.
“Recruitment and activation of microglia around plaques and subsequent Aβ degradation/clearance have been proposed as one of the mechanisms by which Aβ immunotherapy decreases amyloid levels (Bard et al., 2000; Koenigsknecht-Talboo et al., 2008; Wang et al., 2011).”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as Bard et al., 2000
Microglial-mediated phagocytosis is one of the major mechanisms for removal of plaques in response to some anti-Aβ antibodies.
“One of the major mechanisms for removal of the plaques in response to some anti-A antibodies is microglial-mediated phagocytosis (Bard et al., 2000;Demattos et al., 2012).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Bard et al., 2000
10D5 mAb is known to penetrate the blood-brain-barrier (BBB) and directly binds to deposited Aβ triggering microglial cells to clear Aβ plaques through Fc receptor-mediated phagocytosis.
“We used mAb 10D5 direct against Aβ3–7 epitope [10], which is known to penetrate the blood–brain-barrier (BBB) and directly binds to deposited Aβ triggering microglial cells to clear Aβ plaques through Fc receptor-mediated phagocytosis [9].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [9]
The dose of 10D5 mAb used in this study was previously shown to be effective in removing Aβ plaques in PDAPP AD Tg mice expressing wild type murine apoE.
“The dose of 10D5 mAb used in this study was previously shown to be effective in removing Aβ plaques in PDAPP AD Tg mice expressing wild type murine apoE [9, 10, 22].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [9]
The primary mechanism of action of 10D5 mAb is based on its direct binding to deposited Aβ and stimulating Fc receptor-mediated Aβ plaque removal by activated microglia and possibly blood derived macrophages.
“The primary mechanism of action of 10D5 mAb is based on its direct binding to deposited Aβ and stimulating Fc receptor-mediated Aβ plaque removal by activated microglia and possibly blood derived macrophages [9, 34].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [9]
In preclinical studies, the murine form of the antibody 3D6 reduces the amount of Aβ in the brain.
“In preclinical studies, the murine form of the antibody (3D6) was shown to bind to fibrillar, oligomeric, and monomeric forms of Aβ, reduce the amount of Aβ in the brain, and improve memory in transgenic mice that overproduced Aβ.4–8”
From Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease (2014) · cites this paper as [4]
In preclinical studies, the murine form of the antibody 3D6 improves memory in transgenic mice that overproduce Aβ.
“In preclinical studies, the murine form of the antibody (3D6) was shown to bind to fibrillar, oligomeric, and monomeric forms of Aβ, reduce the amount of Aβ in the brain, and improve memory in transgenic mice that overproduced Aβ.4–8”
From Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease (2014) · cites this paper as [4]
In preclinical studies, the murine form of the antibody 3D6 binds fibrillar, oligomeric, and monomeric forms of Aβ.
“In preclinical studies, the murine form of the antibody (3D6) was shown to bind to fibrillar, oligomeric, and monomeric forms of Aβ, reduce the amount of Aβ in the brain, and improve memory in transgenic mice that overproduced Aβ.4–8”
From Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease (2014) · cites this paper as [4]
Experimental therapies such as Aβ immunotherapy reduce cerebral Aβ and improve behavior in transgenic mouse models of AD-like cerebral β-amyloidosis.
“Experimental therapies, such as Aβ immunotherapy [8, 53, 138, 164, 178], were not only shown to reduce cerebral Aβ, but even more importantly, to improve behavior in transgenic mouse models of AD-like cerebral β-amyloidosis.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [8]
Cites
Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., et al. (1999) · Nature · doi:10.1038/22124 · Cited by 3,160 · see citing works
Self-citationAlzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516 · see citing works
Self-citationJohnson‐Wood, K., Lee, M., Motter, R. N., Hu, K., Gordon, G., Barbour, R., Khan, K., Gordon, M. N., Tan, H. T., Games, D., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.4.1550 · Cited by 634 · see citing works
Self-citationMasliah, E., Sisk, A., Mallory, M. E., Mucke, L., Schenk, D., & Games, D. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-18-05795.1996 · Cited by 387 · see citing works
Self-citationSlow Degradation of Aggregates of the Alzheimer's Disease Amyloid β-Protein by Microglial Cells
Paresce, D. M., Chung, H., & Maxfield, F. R. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.46.29390 · Cited by 269 · see citing works
Chung, H., Brazil, M. I., Soe, T. T., & Maxfield, F. R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.45.32301 · Cited by 212 · see citing works
Hyman, B. T., Tanzi, R. E., Marzloff, K., Barbour, R., & Schenk, D. (1992) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199201000-00009 · Cited by 135 · see citing works
Self-citationLaboratory Investigation of Cerebrospinal Fluid Proteins
Thompson, E. J., & Keir, G. (1990) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456329002700503 · Cited by 69 · see citing works
Antibody clears senile plaques
George‐Hyslop, P. S., & Westaway, D. A. (1999) · Nature · doi:10.1038/22006 · Cited by 41 · see citing works
Curing amyloidosis: will it work in humans?
Duff, K. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01489-7 · Cited by 14 · see citing works
Flagged first, then by citations
1 of the 11 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023 · see citing works
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016) · Nature · doi:10.1038/nature19323 · Cited by 3,059 · see citing works
Blennow, K., de Leon, M. J., & Zetterberg, H. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69113-7 · Cited by 3,134 · see citing works
Pathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052 · see citing works
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188 · see citing works
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1304839 · Cited by 1,960 · see citing works
Molecular Mechanisms of Amyloidosis
Merlini, G., & Bellotti, V. (2003) · New England Journal of Medicine · doi:10.1056/nejmra023144 · Cited by 1,927 · see citing works
Overcoming the challenges in administering biopharmaceuticals: Formulation and delivery strategies
Mitragotri, S., Burke, P. A., & Langer, R. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4363 · Cited by 1,702 · see citing works
Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease
Morgan, D., Diamond, D. M., Gottschall, P. E., Ugen, K. E., Dickey, C. A., Hardy, J., Duff, K., Jantzen, P. T., DiCarlo, G., Wilcock, D. M., et al. (2000) · Nature · doi:10.1038/35050116 · Cited by 1,488 · see citing works
Cherny, R. A., Atwood, C. S., Xilinas, M. E., Gray, D. N., Jones, W. D., McLean, C. A., Barnham, K. J., Volitakis, I., Fraser, F. W., Kim, Y.-S., et al. (2001) · Neuron · doi:10.1016/s0896-6273(01)00317-8 · Cited by 1,447 · see citing works
Alzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · see citing works
Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report
Nicoll, J. A. R., Wilkinson, D., Holmes, C., Steart, P., Markham, H., & Weller, R. O. (2003) · Nature Medicine · doi:10.1038/nm840 · Cited by 1,397 · see citing works
DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J.-C., Paul, S. M., & Holtzman, D. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151261398 · Cited by 1,298 · see citing works
Inflammation in Neurodegenerative Disease—A Double-Edged Sword
Wyss-Coray, T., & Mucke, L. (2002) · Neuron · doi:10.1016/s0896-6273(02)00794-8 · Cited by 1,235 · see citing works
Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
Walsh, D. M., & Selkoe, D. J. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.010 · Cited by 1,207 · see citing works
Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease
Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., et al. (2000) · Nature · doi:10.1038/35050110 · Cited by 1,431 · see citing works
Alzheimer's disease: strategies for disease modification
Citron, M. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd2896 · Cited by 1,060 · see citing works
Systemic infections and inflammation affect chronic neurodegeneration
Perry, V. H., Cunningham, C., & Holmes, C. (2007) · Nature Reviews Immunology · doi:10.1038/nri2015 · Cited by 1,027 · see citing works
Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?
Klein, W. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01749-5 · Cited by 989 · see citing works
Inflammation in Alzheimer Disease--A Brief Review of the Basic Science and Clinical Literature
Wyss-Coray, T., & Rogers, J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006346 · Cited by 975 · see citing works
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“In the preclinical studies, 3D6 binds to monomeric, oligomeric and fibril forms of Aβ, leading to the reduced levels of Aβ and improved cognitive deficits in AD model mice.(334) However, the Phase 3 clinical trials revealed that bapineuzumab could not improve clinical outcomes in mild to moderate AD patients.”
BackgroundChishti, M. A., Yang, D.-S., Janus, C., Phinney, A. L., Horne, P., Pearson, J., Strome, R., Zuker, N., Loukides, J., French, J., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100710200 · Cited by 955 · see citing works
El Khoury, J., Toft, M., Hickman, S. E., Means, T. K., Terada, K., Geula, C., & Luster, A. D. (2007) · Nature Medicine · doi:10.1038/nm1555 · Cited by 915 · see citing works
Adult mouse astrocytes degrade amyloid-β in vitro and in situ
Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F., Silverstein, S. C., & Husemann, J. (2003) · Nature Medicine · doi:10.1038/nm838 · Cited by 909 · see citing works
The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization
Hamley, I. W. (2012) · Chemical Reviews · doi:10.1021/cr3000994 · Cited by 881 · see citing works
Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · see citing works
Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model
Dodart, J.-C., Bales, K. R., Gannon, K. S., Greene, S. J., DeMattos, R. B., Mathis, C., DeLong, C. A., Wu, S., Wu, X., Holtzman, D. M., et al. (2002) · Nature Neuroscience · doi:10.1038/nn842 · Cited by 858 · see citing works
UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis
Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K., Shinozaki, Y., Ohsawa, K., Tsuda, M., Joshi, B. V., Jacobson, K. A., Kohsaka, S., & Inoue, K. (2007) · Nature · doi:10.1038/nature05704 · Cited by 802 · see citing works
Alzheimer's Disease: Molecular Understanding Predicts Amyloid-Based Therapeutics
Selkoe, D. J., & Schenk, D. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.140248 · Cited by 816 · see citing works
Self-citationThe amyloid hypothesis for Alzheimer’s disease: A critical reappraisal
Hardy, J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06181.x · Cited by 814 · see citing works
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., & LaFerla, F. M. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.003 · Cited by 780 · see citing works
Ramírez, B. G., Blázquez, C., del Pulgar, T. G., Guzmán, M., & CEBALLOS, M. L. D. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4540-04.2005 · Cited by 783 · see citing works
Antibodies against β-Amyloid Slow Cognitive Decline in Alzheimer's Disease
Höck, C., Konietzko, U., Streffer, J. R., Tracy, J., Signorell, A., Müller-Tillmanns, B., Lemke, U., Henke, K., Moritz, E., Garcia, E., et al. (2003) · Neuron · doi:10.1016/s0896-6273(03)00294-0 · Cited by 777 · see citing works
Glycogen synthase kinase-3 (GSK3): Inflammation, diseases, and therapeutics
Jope, R. S., Yuskaitis, C. J., & Beurel, E. (2007) · Neurochemical Research · doi:10.1007/s11064-006-9128-5 · Cited by 774 · see citing works
Does neuroinflammation fan the flame in neurodegenerative diseases?
Frank-Cannon, T. C., Alto, L. T., McAlpine, F. E., & Tansey, M. G. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-47 · Cited by 751 · see citing works
Protein aggregation diseases: pathogenicity and therapeutic perspectives
Aguzzi, A., & O’Connor, T. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3050 · Cited by 750 · see citing works
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics
Karran, E., & De Strooper, B. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00391-w · Cited by 742 · see citing works
A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease
Salloway, S., Sperling, R., Gilman, S., Fox, N. C., Blennow, K., Raskind, M., Sabbagh, M., Honig, L. S., Doody, R., van Dyck, C. H., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181c67808 · Cited by 753 · see citing works
Self-citationThe biphasic function of microglia in ischemic stroke
Ma, Y., Wang, J., Wang, Y., & Yang, G. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.005 · Cited by 724 · see citing works
The role of inflammation in Alzheimer’s disease
Tuppo, E. E., & Arias, H. R. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.07.009 · Cited by 734 · see citing works
Treatment of Alzheimer's disease; current status and new perspectives
Scarpini, E. A., Scheltens, P., & Feldman, H. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00502-7 · Cited by 720 · see citing works
Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., & Selkoe, D. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00787-6 · Cited by 708 · see citing works
Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., & LaFerla, F. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2868-05.2005 · Cited by 697 · see citing works
Rinne, J. O., Brooks, D. J., Rossor, M. N., Fox, N. C., Bullock, R., Klunk, W. E., Mathis, C. A., Blennow, K., Barakos, J., Okello, A. A., et al. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70043-0 · Cited by 701 · see citing works
Self-citationThe role of microglia in amyloid clearance from the AD brain
Lee, C. Y. D., & Landreth, G. E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0433-4 · Cited by 701 · see citing works
The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
Oliver, G. C., Kipnis, J., Randolph, G. J., & Harvey, N. L. (2020) · Cell · doi:10.1016/j.cell.2020.06.039 · Cited by 685 · see citing works
A century-old debate on protein aggregation and neurodegeneration enters the clinic
Lansbury, P. T., & Lashuel, H. A. (2006) · Nature · doi:10.1038/nature05290 · Cited by 681 · see citing works
Animal models of Alzheimer's disease and frontotemporal dementia
Götz, J., & Ittner, L. M. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2420 · Cited by 676 · see citing works
Garcı́a-Alloza, M., Borrelli, L. A., Rozkalne, A., Hyman, B. T., & Bacskai, B. J. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04613.x · Cited by 663 · see citing works
Phagocytosis of Microglia in the Central Nervous System Diseases
Fu, R., Shen, Q., Xu, P., Luo, J. J., & Tang, Y. (2014) · Molecular Neurobiology · doi:10.1007/s12035-013-8620-6 · Cited by 646 · see citing works
Alzheimer's Disease: From Pathology to Therapeutic Approaches
Jakob‐Roetne, R., & Jacobsen, H. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200802808 · Cited by 626 · see citing works
Yanamandra, K., Kfoury, N., Jiang, H., Mahan, T. E., Ma, S., Maloney, S. E., Wozniak, D. F., Diamond, M. I., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.046 · Cited by 574 · see citing works
Anti-Amyloid-β Monoclonal Antibodies for Alzheimer’s Disease: Pitfalls and Promise
van Dyck, C. H. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.010 · Cited by 568 · see citing works
TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice
Wyss-Coray, T., Lin, C., Yan, F., Yu, G.-Q., Rohde, M., McConlogue, L., Masliah, E., & Mucke, L. (2001) · Nature Medicine · doi:10.1038/87945 · Cited by 587 · see citing works
Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638 · see citing works
A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease
for the SCarlet RoAD Investigators, Ostrowitzki, S., Lasser, R. A., Dorflinger, E., Scheltens, P., Barkhof, F., Nikolcheva, T., Ashford, E., Retout, S., Hofmann, C., et al. (2017) · Alzheimer's Research & Therapy · doi:10.1186/s13195-017-0318-y · Cited by 567 · see citing works
Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides
Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K. R., et al. (2004) · Nature Medicine · doi:10.1038/nm1058 · Cited by 571 · see citing works
Ferrer, I., Boada, M., Guerra, M. L. S., Rey, M. J., & Costa‐Jussà, F. R. (2004) · Brain Pathology · doi:10.1111/j.1750-3639.2004.tb00493.x · Cited by 567 · see citing works
The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective
Shaftel, S. S., Griffin, W. S. T., & O'Banion, M. K. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-7 · Cited by 565 · see citing works
100 Years and Counting: Prospects for Defeating Alzheimer's Disease
Roberson, E. D., & Mucke, L. (2006) · Science · doi:10.1126/science.1132813 · Cited by 550 · see citing works
Deane, R., Bell, R. D., Sagare, A. P., & Zloković, B. V. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787601867 · Cited by 549 · see citing works
Clearing the brain's amyloid cobwebs
Selkoe, D. J. (2001) · Neuron · doi:10.1016/s0896-6273(01)00475-5 · Cited by 541 · see citing works
Castellani, R. J., Rolston, R. K., & Smith, M. A. (2010) · Disease-a-Month · doi:10.1016/j.disamonth.2010.06.001 · Cited by 561 · see citing works
Antibodies inhibit prion propagation and clear cell cultures of prion infectivity
Peretz, D., Williamson, R. A., Kaneko, K., Vergara, J. A., Leclerc, E., Schmitt‐Ulms, G., Mehlhorn, I., Legname, G., Wormald, M. R., Rudd, P. M., et al. (2001) · Nature · doi:10.1038/35089090 · Cited by 517 · see citing works
Mechanisms of Aβ Clearance and Degradation by Glial Cells
Ries, M., & Sastre, M. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00160 · Cited by 527 · see citing works
“The FcRs have been shown to mediate Aβ clearance in the presence of anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2003), as observed in Aβ immunization therapies (Bacskai et al., 2002).”
BackgroundPhenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology
Frautschy, S. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00300-1 · Cited by 514 · see citing works
Alzheimer's disease – do tauists and baptists finally shake hands?
Mudher, A. K., & Lovestone, S. (2002) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)02031-2 · Cited by 512 · see citing works
Edison, P., Archer, H. A., Gerhard, A., Hinz, R., Pavese, N., Turkheimer, F. E., Hammers, A., Tai, Y. F., Fox, N., Kennedy, A., et al. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.08.001 · Cited by 513 · see citing works
γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?
Sisodia, S. S., & St George-Hyslop, P. H. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn785 · Cited by 512 · see citing works
Protective and therapeutic role for αB-crystallin in autoimmune demyelination
Ousman, S., Tomooka, B. H., van Noort, J., Wawrousek, E., O'Conner, K., Hafler, D., Sobel, R., Robinson, W., & Steinman, L. (2007) · Nature · doi:10.1038/nature05935 · Cited by 491 · see citing works
Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease
Nagele, R. G., Węgiel, J., Venkataraman, V., Imaki, H., Wang, K.-C., & Wegiel, J. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.01.007 · Cited by 497 · see citing works
Monoclonal antibodies inhibit prion replication and delay the development of prion disease
White, A. R., Enever, P., Tayebi, M., Mushens, R., Linehan, J., Brandner, S., Anstee, D. J., Collinge, J., & Hawke, S. H. (2003) · Nature · doi:10.1038/nature01457 · Cited by 490 · see citing works
Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo
Klyubin, I., Walsh, D. M., Lemere, C. A., Cullen, W. K., Shankar, G. M., Betts, V., Spooner, E. T., Jiang, L., Anwyl, R., Selkoe, D. J., et al. (2005) · Nature Medicine · doi:10.1038/nm1234 · Cited by 489 · see citing works
Alzheimer disease therapy—moving from amyloid-β to tau
Giacobini, E., & Gold, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.223 · Cited by 483 · see citing works
Koenigsknecht-Talboo, J., & Landreth, G. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1808-05.2005 · Cited by 477 · see citing works
A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice
DeMattos, R. B., Lu, J., Tang, Y., Racke, M. M., DeLong, C. A., Tzaferis, J. A., Hole, J. T., Forster, B. M., McDonnell, P. C., Liu, F., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.10.029 · Cited by 442 · see citing works
Suh, Y.-H., & Checler, F. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.3.469 · Cited by 467 · see citing works
Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice
Wyss-Coray, T., Yan, F., Lin, A. H.-T., Lambris, J. D., Alexander, J. J., Quigg, R. J., & Masliah, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162350199 · Cited by 446 · see citing works
Bohrmann, B., Baumann, K., Benz, J., Gerber, F., Huber, W., Knoflach, F., Messer, J., Oroszlan, K., Rauchenberger, R., Richter, W. F., et al. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-110977 · Cited by 448 · see citing works
The microglial "activation" continuum: from innate to adaptive responses
Town, T., Nikolic, V., & Tan, J. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-24 · Cited by 456 · see citing works
Bacskai, B. J., Kajdasz, S. T., Christie, R. H., Carter, C., Games, D., Seubert, P. A., Schenk, D., & Hyman, B. T. (2001) · Nature Medicine · doi:10.1038/85525 · Cited by 445 · see citing works
Self-citationDynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance
Bolmont, T., Haiss, F., Eicke, D., Radde, R., Mathis, C. A., Klunk, W. E., Kohsaka, S., Jucker, M., & Calhoun, M. E. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4814-07.2008 · Cited by 526 · see citing works
TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation
Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rübe, C. E., Walter, J., Heneka, M. T., Hartmann, T., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101121 · Cited by 439 · see citing works
Role of toll-like receptor signalling in A uptake and clearance
Tahara, K., Kim, H.-D., Jin, J.-J., Maxwell, J. A., Li, L., & Fukuchi, K.-I. (2006) · Brain · doi:10.1093/brain/awl249 · Cited by 493 · see citing works
Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism
Koenigsknecht-Talboo, J., & Landreth, G. E. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2557-04.2004 · Cited by 444 · see citing works
Alpha 1 -Antitrypsin Deficiency — A Model for Conformational Diseases
Carrell, R. W., & Lomas, D. A. (2002) · New England Journal of Medicine · doi:10.1056/nejmra010772 · Cited by 447 · see citing works
Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases
Mandel, S. A., & Youdim, M. B. H. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.04.012 · Cited by 443 · see citing works
Potassium channel antibodies in two patients with reversible limbic encephalitis
Buckley, C. J., Oger, J., Clover, L. M., Tüzün, E., Carpenter, K., Jackson, M., & Vincent, A. C. (2001) · Annals of Neurology · doi:10.1002/ana.1097 · Cited by 444 · see citing works
Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis
Pepys, M. B., Herbert, J., Hutchinson, W. L., Tennent, G. A., Lachmann, H. J., Gallimore, J. R., Lovat, L. B., Bartfai, T., Alanine, A., Hertel, C., et al. (2002) · Nature · doi:10.1038/417254a · Cited by 540 · see citing works
Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning
Schenk, D. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn938 · Cited by 436 · see citing works
Self-citationAlzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers
De Felice, F. G., Wu, D., Lambert, M. P., Fernandez, S. J., Velasco, P. T., Lacor, P. N., Bigio, E. H., Jerecic, J., Acton, P. J., Shughrue, P. J., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.02.029 · Cited by 432 · see citing works
Genetically Engineered Phages: a Review of Advances over the Last Decade
Pires, D. P., Cleto, S., Sillankorva, S., Azeredo, J., & Lu, T. K. (2016) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00069-15 · Cited by 441 · see citing works
Edison, P., Rowe, C. C., Rinne, J. O., Ng, S., Ahmed, I., Kemppainen, N. M., Villemagne, V. L., O'Keefe, G. J., Någren, K., Chaudhuri, К. R., et al. (2008) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2007.127878 · Cited by 422 · see citing works
Strategies for disease modification in Alzheimer's disease
Citron, M. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1495 · Cited by 426 · see citing works
Enari, M., Flechsig, E., & Weissmann, C. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151242598 · Cited by 427 · see citing works
- Authors
- Bard, F., Cannon, C., Barbour, R., Burke, R.-L., 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., & Yednock, T.
- Affiliations
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Corresponding author
- Bard, Frédérique
- Venue
- Nature Medicine
- Published
- 2000-08
- Volume
- 6
- Issue
- 8
- Pages
- 916-919
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1567490604
- Cited by
- 2,012
- References
- 11
- Citations by year
- 2026: 23 · 2025: 36 · 2024: 38 · 2023: 41 · 2022: 49 · 2021: 32 · 2020: 73 · 2019: 46 · 2018: 41 · 2017: 48 · 2016: 76 · 2015: 66 · 2014: 107 · 2013: 89 · 2012: 107
- FWCI
- 67.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, passive immunization, anti-amyloid antibodies, blood-brain barrier penetration, amyloid plaques, microglial phagocytosis, Fc receptors, PDAPP mice, amyloid precursor protein, plaque clearance, antibody therapy
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Disease Models, Animal, Humans, Immunization, Mice, Transgenic, Phagocytosis, Amyloid beta-Peptides, Mice, Plaque, Amyloid, In Vitro Techniques
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