Four-dimensional microglia response to anti-Aβ treatment in APP/PS1xCX3CR1/GFP mice

Senile plaques, mainly composed of amyloid-β (Aβ), are a major hallmark of Alzheimer disease (AD), and immunotherapy is a leading therapeutic approach for Aβ clearance. Although the ultimate mechanisms for Aβ clearance are not well known, characteristic microglia clusters are observed in the surround of senile plaques, and are implicated both in the elimination of Aβ as well as the deleterious inflammatory effects observed in AD patients after active immunization. Therefore, analyzing the direct effect of immunotherapy on microglia, using longitudinal in vivo multiphoton microscopy can provide important information regarding the role of microglia in immunotherapy. While microglia were observed to surround senile plaques, topical anti-Aβ antibody administration, which led to a reduction in plaque size, directed microglia toward senile plaques, and the overall size of microglia and number of processes were increased. In some cases, we observed clusters of microglia in areas of the brain that did not have detectable amyloid aggregates, but this did not predict the deposition of new plaques in the area within a week of imaging, indicating that microglia react to but do not precipitate amyloid aggregation. The long-term presence of large microglial clusters in the surrounding area of senile plaques suggests that microglia cannot effectively remove Aβ unless anti-Aβ antibody is administered. All together, these data suggest that although there is a role for microglia in Aβ clearance, it requires an intervention like immunotherapy to be effective.