Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
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.
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA. fbard@elanpharma.com
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Bard
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Cannon
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Barbour
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Burke
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Games
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Grajeda
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Guido
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Hu
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Huang
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Johnson-Wood
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Khan
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Kholodenko
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Lee
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Lieberburg
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Motter
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Nguyen
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Soriano
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Vasquez
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Weiss
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Welch
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Seubert
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Schenk
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Yednock
D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007114:Immunization; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000276:immunology / Q000473:pathology
D016229:Amyloid beta-Peptides; D000906:Antibodies