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Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease

Abstract

Much evidence indicates that abnormal processing and extracellular deposition of amyloid-β peptide (Aβ), a proteolytic derivative of the β-amyloid precursor protein (βAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with Aβ causes a marked reduction in burden of the brain amyloid2,3. Evidence that Aβ immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal Aβ processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the ‘amyloid cascade’. Here we show that Aβ immunization reduces both deposition of cerebral fibrillar Aβ and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of Aβ in the brain. This implies that either a 50% reduction in dense-cored Aβ plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic Aβ species.

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Figure 1: Aβ and IAPP peptide immunogens were predominantly β-structured and induced antibodies recognizing fibrillar Aβ deposits.
Figure 2: Reference memory version of Morris water maze test in TgCRND8 mice.
Figure 3: At 25 weeks of age, in TgCRND8 mice immunized with Aβ42 peptides, dense-cored Aβ plaque burden is reduced in the hippocampus (HIPP) (a) and in the cerebral cortex (CTX) (b).

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Acknowledgements

This work was supported by the Medical Research Council of Canada, Howard Hughes Medical Research Foundation, Alzheimer Society of Ontario, The W. Garfield Weston Foundation and the US National Institute of Aging. We thank G. Carlson for useful discussions, and R. Renlund, K. Parisien, J. Haight and J. Cowieson for help during mice immunization. None of the authors has a financial or other relationship with Elan Pharmaceuticals Inc.

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Janus, C., Pearson, J., McLaurin, J. et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979–982 (2000). https://doi.org/10.1038/35050110

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