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

Abstract

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.

In Vivo Imaging of Microglia With Multiphoton Microscopy

“…It was also implied that microglia do not successfully clear plaques, unless further activated, suggesting that they restrict senile plaque growth instead, and contribute to the steady state of plaque size after initial formation (Meyer-Luehmann et al, 2008 ). Other studies have shown similar results, and chronic in vivo imaging of microglia clusters did not predict the deposition of new senile plaques (Garcia-Alloza et al, 2013 ), as can be observed in Figure 3 . Comparable observations have also been reported in other AD models (APP/PS1×Iba-1-GFP mice) after long-term in vivo microglia imaging (Bolmont et al, 2008 ).…”

“…It has also been shown that direct administration of anti-Aβ antibodies to APP/PS1/CX3CR1-GFP mice increases microglia size and the number of processes in the close proximity to senile plaques within 1 week. A tendency towards increasing the numbers of cells located in the immediate surround of the senile plaques was also observed (Garcia-Alloza et al, 2013 ). The fact that senile plaques were not cleared in untreated mice, even though extensive microglia numbers were detected around amyloid deposits, supports the idea that mechanisms, both dependent and independent of microglia, may act in the immunotherapy mediated clearance of Aβ plaque (Garcia-Alloza et al, 2013 ).…”

“…Despite the relevant role that microglia play in AD, only a handful of studies have analyzed these cells using in vivo MPM. Most of this work has focused on the role that microglia plays in reducing or exacerbating amyloid pathology (Meyer-Luehmann et al, 2008 ; Venneti et al, 2009 ) or the implication of microglial cells in the clearing process after anti-Aβ treatments (Koenigsknecht-Talboo et al, 2008 ; Garcia-Alloza et al, 2013 ).…”

“…Anti-Aβ immunotherapy triggered an increased interest in the role of microglia as the mediators of neuroinflammation in the AD brain. In this regard, a comprehensive analysis of the underlying mechanisms of antibody-mediated clearance and microglia activation could improve immunotherapy treatments for AD, while avoiding negative inflammatory side effects (Garcia-Alloza et al, 2013 ). The direct effect of anti-Aβ antibodies on amyloid deposition and clearance has been followed in detail in vivo and in real time with MPM (Bacskai et al, 2002 ; Prada et al, 2007 ).…”

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

“…It has been reported that microglia may try to clear A␤ (Morgan, 2006) in order to remove amyloid pathology. As such, microglia seem to play a dual role, and whereas they might control SP deposition, this effect seems to be unsuccessful as the disease progresses and inflammatory deleterious effects, derived from microglia activation, are more prone to appear (Garcia-Alloza et al, 2007;Garcia-Alloza et al, 2013).…”