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

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          Abstract

          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 Aβ 40-DI, Aβ 42, 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.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          5 December 2007
          : 27
          : 49
          : 13376-13383
          Affiliations
          [1] 1The Institute for Brain Aging and Dementia and
          [2] 2Department of Neurology, University of California, Irvine, Irvine, California 92697-4540, and
          [3] 3Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153
          Author notes
          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. cribbs@ 123456uci.edu
          Article
          PMC6673094 PMC6673094 6673094 3282745
          10.1523/JNEUROSCI.2788-07.2007
          6673094
          18057195
          137da4e3-40b9-4f1e-b43d-ae09fa792507
          Copyright © 2007 Society for Neuroscience 0270-6474/07/2713376-08$15.00/0
          History
          : 19 June 2007
          : 18 September 2007
          : 25 September 2007
          Categories
          Articles
          Neurobiology of Disease

          blood–brain barrier,Alzheimer's disease,transgenic animal model,epitope vaccine,immunotherapy,peripheral sink,β-amyloid

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