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The Journal of Neuroscience, December 5, 2007, 27(49):13376-13383; doi:10.1523/JNEUROSCI.2788-07.2007

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Neurobiology of Disease
Experimental Investigation of Antibody-Mediated Clearance Mechanisms of Amyloid-β in CNS of Tg-SwDI Transgenic Mice

Vitaly Vasilevko,¹ Feng Xu,³ Mary Lou Previti,³ William E. Van Nostrand,³ and David H. Cribbs^1,2

¹The Institute for Brain Aging and Dementia and ²Department of Neurology, University of California, Irvine, Irvine, California 92697-4540, and ³Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153

Correspondence should be addressed to Dr. David H. Cribbs, Institute for Brain Aging and Dementia, Department of Neurology, University of California, Irvine, 1207 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540. Email: cribbs{at}uci.edu

Novel amyloid precursor protein transgenic mice, which contain the Swedish as well as the vasculotropic Dutch and Iowa mutations (Tg-SwDI), were used to investigate the mechanisms of antibody-mediated clearance of amyloid-β (Aβ) from the brain. Export of the Aβ-DI peptide across the blood–brain barrier is severely reduced because of the vasculotropic mutations. Therefore, antibody-mediated clearance of Aβ-DI is dependent on antibodies entering the brain. In this report, we immunized Tg-SwDI mice with various peptide antigens, including Aβ₄₀-DI, Aβ₄₂, and an Aβ epitope vaccine. Immunization of Tg-SwDI mice with substantial cortical diffuse and vascular fibrillar deposits failed to promote clearance of parenchymal or vascular amyloid deposits. We then immunized young Tg-SwDI mice before the accumulation of Aβ and saw no evidence that anti-Aβ antibodies could diminish deposition of parenchymal or vascular amyloid deposits. However, injection of anti-Aβ antibodies, affinity-purified from immunized Tg-SwDI mice, into the hippocampus induced a rapid clearance of diffuse Aβ deposits but not vascular amyloid deposits. These results further support the "peripheral sink hypothesis" as a legitimate mechanism of antibody-mediated clearance of Aβ when the blood–brain barrier remains intact. Thus, approaches that deliver immunotherapy to the brain may be more effective at clearing Aβ than immunization strategies in which the majority of the antibodies are in the periphery.

Key words: immunotherapy; epitope vaccine; transgenic animal model; Alzheimer's disease; β-amyloid; blood–brain barrier; peripheral sink

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Received June 19, 2007; revised Sept. 18, 2007; accepted Sept. 25, 2007.

Correspondence should be addressed to Dr. David H. Cribbs, Institute for Brain Aging and Dementia, Department of Neurology, University of California, Irvine, 1207 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540. Email: cribbs{at}uci.edu

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