| Alzheimer's disease (AD) is the most common dementia, characterized by amyloid plaques, tangles and neuronal loss in the brain. Amyloid plaques consist primarily of Abeta1-42, and the aggregation of this peptide is implicated as a pathogenic factor. Abeta immunotherapy utilizes Abeta-specific antibodies to clear Abeta, leading to cognitive improvement in AD mouse models. However, a patient trial of Abeta vaccination had to be stopped due to meningoencephalitis.;The mechanisms of Abeta clearance must be determined to ensure the safety and efficacy of Abeta immunotherapy. Further, it must be established if immunotherapy can clear pre-existing amyloid plaques, or if it must be administered as a prophylactic. Because Abeta antibodies elevate Abeta in the blood, this strategy has been suggested as a diagnostic test for AD, but epitope-overlap may reduce its sensitivity.;We have examined the role of microglia in Abeta clearance after immunotherapy in vitro and in vivo, the effects of Abeta antibodies on pre-existing amyloid plaques, and Abeta antibodies as a diagnostic modality using mouse models of AD.;We demonstrate that Abeta antibodies do not enhance microglial phagocytosis of Abeta-coated beads in vitro, or increase microglial activation around amyloid plaques in vivo. Ablating FcgammaRIIB, a negative regulator of FcgammaRI and FcgammaRIII, is not sufficient to enhance antibody-mediated Abeta clearance in vivo. Secondly, we observe no amyloid reductions after immunotherapy in one mouse model where Abeta production was suppressed, whereas small but statistically significant reductions were observed in another model with constitutive Abeta production. Lastly, we find that administration of Abetaantibodies result in the detection of an antibody-Abeta complex in the plasma of transgenic AD mice, but also in non-transgenic mice.;We conclude that microglial activation may not be the primary mediator of Abeta clearance after Abeta immunotherapy. Further, since immunotherapy results in limited clearance of pre-existing amyloid plaques, this therapy may be best suited as a prophylactic. A consistent trend in our studies is the variability in the response of different mouse models to Abeta immunotherapy. Therefore, it is essential that immunotherapy is evaluated in several mouse models of AD to develop a safe and effective treatment. |
