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Aß peptide immunization restores blood-brain barrier integrity in Alzheimer disease

Dara L. Dickstein^*,,, Kaan E. Biron^*,,, Maki Ujiie^*,, Cheryl G. Pfeifer^*,, Andrew R. Jeffries^*, and Wilfred A. Jefferies^*,,,,||,1

^* Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada;
Biomedical Research Centre, University of British Columbia, Vancouver, Canada;
Department of Medical Genetics, University of British Columbia, Vancouver, Canada;
Department of Microbiology & Immunology, University of British Columbia, Vancouver, Canada; and
^|| Department of Zoology, University of British Columbia, Vancouver, Canada

¹Correspondence: The Michael Smith Laboratories, 2185 East Mall, Vancouver, BC, Canada, V6T 1Z4. E-mail: wilf{at}brc.ubc.ca

Immunization with amyloid beta (Aß) peptides or passive immunization with antibodies against Aß has been reported to reduce plaque burden, neuritic dystrophy, early Tau pathology, microgliosis as well as reversing learning and memory deficits. This has created a central paradox: how does vaccination in peripheral tissues reduce plaque burden in the brain? No single explanation for these phenomena has yet been presented. To reconcile these observations, we demonstrate that the integrity of the blood-brain barrier (BBB), a structural barrier between the brain and the blood, is compromised in Tg2576 Alzheimer disease (AD) model mice. We immunized Tg2576 mice with Aß before and after the onset of AD-type neuropathology and observed that BBB permeability, amyloid burden, and microgliosis are decreased in immunized mice. It is concluded that the integrity of the BBB is disrupted in AD mice, and after Aß immunization the immune system clears Aß from sources in the brain as it would in peripheral organs lacking barriers. Once Aß is removed, the integrity of the BBB is restored. The data therefore provide an intellectual framework for understanding how the immune system can clear amyloid deposits from AD brains and suggest new strategies for limiting disease progression in amyloidopathies.—Dickstein, D. L., Biron, K. E., Ujiie, M., Pfeifer, C. G., Jeffries, A. R., Jefferies, W. A. Aß peptide immunization restores blood-brain barrier integrity in Alzheimer disease.

Key Words: brain • microcirculation • vaccination • plaques

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