Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
Elan Pharmaceuticals, South San Francisco, California 94080, USA. dschenk@elanpharma.com
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Schenk
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Barbour
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Dunn
G
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Gordon
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Grajeda
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Guido
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Hu
J
J
Huang
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Johnson-Wood
K
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Khan
D
D
Kholodenko
M
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Lee
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Liao
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Lieberburg
R
R
Motter
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Mutter
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Soriano
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Shopp
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Vasquez
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Vandevert
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Walker
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Wogulis
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Yednock
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Games
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Seubert
D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000473:pathology; D002021:Buffers; D004797:Enzyme-Linked Immunosorbent Assay; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D017354:Point Mutation; D000683:Serum Amyloid P-Component / Q000008:administration & dosage / Q000276:immunology; D014611:Vaccination
D016229:Amyloid beta-Peptides; D002021:Buffers; D010446:Peptide Fragments; D000683:Serum Amyloid P-Component; C075222:amyloid beta-protein (1-42); D005620:Freund's Adjuvant