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The Journal of Neuroscience, July 7, 2004, 24(27):6144-6151; doi:10.1523/JNEUROSCI.1090-04.2004

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Neurobiology of Disease
Passive Amyloid Immunotherapy Clears Amyloid and Transiently Activates Microglia in a Transgenic Mouse Model of Amyloid Deposition

Donna M. Wilcock,1,2 Amyn Rojiani,1,3,4 Arnon Rosenthal,5 Gil Levkowitz,5 Sangeetha Subbarao,5 Jennifer Alamed,1,2 David Wilson,1,2 Nedda Wilson,1,2 Melissa J. Freeman,1,2 Marcia N. Gordon,1,2 and Dave Morgan1,2

1Alzheimer's Research Laboratory and Departments of 2Pharmacology, 3Interdisciplinary Oncology, and 4Pathology, University of South Florida, Tampa, Florida 33612, and 5Rinat Neuroscience Corporation, Palo Alto, California 94304

The role of microglia in the removal of amyloid deposits after systemically administered anti-A{beta} antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-A{beta} antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-A{beta} antibody but not in those treated with a control antibody. We found that Fc{gamma} receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum A{beta} levels and anti-A{beta} antibody levels were elevated to similar levels at all three survival times in mice given anti-A{beta} injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the A{beta} and resulting in Fc{gamma} receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-A{beta} antibody-mediated amyloid removal can be simultaneously active.

Key words: Alzheimer's disease; antibody; behavior; microglia; immunization; amyloid {beta}

Received March 24, 2004; revised May 12, 2004; accepted May 13, 2004.




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