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 Aβ1-42, and the aggregation of this peptide is implicated as a pathogenic factor. Aβ immunotherapy utilizes Aβ-specific antibodies to clear Aβ, leading to cognitive improvement in AD mouse models. However, a patient trial of Aβ vaccination had to be stopped due to meningoencephalitis.
The mechanisms of Aβ clearance must be determined to ensure the safety and efficacy of Aβ immunotherapy. Further, it must be established if immunotherapy can clear pre-existing amyloid plaques, or if it must be administered as a prophylactic. Because Aβ antibodies elevate Aβ 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 Aβ clearance after immunotherapy in vitro and in vivo, the effects of Aβ antibodies on pre-existing amyloid plaques, and Aβ antibodies as a diagnostic modality using mouse models of AD.
We demonstrate that Aβ antibodies do not enhance microglial phagocytosis of Aβ-coated beads in vitro, or increase microglial activation around amyloid plaques in vivo. Ablating FcγRIIB, a negative regulator of FcγRI and FcγRIII, is not sufficient to enhance antibody-mediated Aβ clearance in vivo. Secondly, we observe no amyloid reductions after immunotherapy in one mouse model where Aβ production was suppressed, whereas small but statistically significant reductions were observed in another model with constitutive Aβ production. Lastly, we find that administration of Aβantibodies result in the detection of an antibody-Aβ 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 Aβ clearance after Aβ 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 Aβ immunotherapy. Therefore, it is essential that immunotherapy is evaluated in several mouse models of AD to develop a safe and effective treatment.
|Advisor:||Troncoso, Juan C., Borchelt, David R.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 69/05, Dissertation Abstracts International|
|Keywords:||Alzheimer's disease, Amyloid-beta, Immunotherapy|
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