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Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse

Abstract

Amyloid-β peptide (Aβ) seems to have a central role in the neuropathology of Alzheimer's disease (AD)1. Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes2,3. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Aβ42)4,5,6,7,8, which is the predominant form found in the amyloid plaques of Alzheimer's disease9,10. 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 manner11,12. In the present study, transgenic animals were immunized with Aβ42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-β deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of β-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-β may be effective in preventing and treating Alzheimer's disease.

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Figure 1: Reduction of Aβ burden in the hippocampus at 13 months of age in mice immunized with Aβ42.
Figure 2: Hippocampal Aβ deposition, neuritic plaque formation and cortical astrocytosis in PBS- and Aβ42-injected mice.
Figure 3: Quantitative image analysis of the cortical Aβ burden in older PBS- and Aβ-treated mice.
Figure 4: Reduction of cortical Aβ deposition in older PDAPP mice immunized with Aβ42.
Figure 5: Reduction of Aβ burden in the entorhinal and retrosplenial cortex of older PDAPP mice following Aβ injection.
Figure 6: Altered Aβ burden in the hippocampus of older Aβ42-treated mice.

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Acknowledgements

We thank Rae Lyn Burke for helpful comments.

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Correspondence to Dale Schenk.

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Schenk, D., Barbour, R., Dunn, W. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999). https://doi.org/10.1038/22124

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