Notably, none of these microglia-hobbling conditions completely prevented the emergence of plaques within wild-type grafts, hinting that other mechanisms of Aβ dissemination, such as diffusion or transport via astrocytes, might also contribute. Finally, when the researchers wiped out 80 percent of microglia by treating 5xFAD mice with the CSF1R inhibitor BLZ945, they stymied Aβ plaque growth within the grafts. The same was true when 5xFAD hosts lacked Irf8, a gene that promotes microglial branching and motility (see image above). In old 5xFAD mice, whose microglial phagocytose poorly, fewer Aβ plaques formed in the wild-type grafts. They used several models to test the idea. If microglia play a role in delivering Aβ into wild-type grafts, then sapping the cells' function should stifle this activity, the researchers reasoned. In 5xFAD mice lacking Irf8 (bottom), microglia largely stay put and plaques do not grow in the graft. In 5xFAD mice (top), microglia (green) infiltrate wild-type graft (dotted line), where A β plaques (red) soon emerge. Using RNA sequencing to compare the transcriptomes of microglia within and outside of the grafts, the researchers found remarkably similar gene-expression profiles between the two, suggesting that once inside the grafts, host microglia behaved similarly to their counterparts outside of the graft. Small particles of Aβ were seen inside of, or closely associated with, some of the infiltrating microglia.Īs plaques grew inside the grafts, more microglia rallied to surround the plaques. Instead, the researchers observed massive infiltration of host microglia to the grafts' border regions. How did the plaques manage to invade wild-type grafts? Using different fluorescent markers to distinguish donor versus host cells, the scientists found that very few axons projected from 5xFAD host neurons into the graft, suggesting that Aβ was unlikely to come from host neurons. Here, too, the researchers found that plaques cropped up in the graft a month after transplant, where they grew over time. As a graduate student in Mathias Jucker’s lab nearly two decades ago, Meyer-Luehmann had used a grafting model to show that Aβ from the host could infiltrate the graft and seed plaques ( Mar 2003 news). To model this scenario, they transplanted embryonic neuronal cells from wild-type mice into young 5xFAD mice that had no amyloid plaques yet. Others have found that microglia release Aβ-containing protein complexes that seed plaques ( Dec 2017 news).įirst author Paolo d’Errico and colleagues investigated whether microglia promote Aβ deposition in plaque-free regions of the brain. Similarly, microglia may help build plaques by ingesting Aβ aggregates and regurgitating them in a more inert, compact form, or they may form a barrier around plaques, keeping them contained ( Apr 2021 news May 2016 news). For one, complete ablation of microglia from the mouse brain prevents the growth of dense core plaques, leading to Aβ accumulation in blood vessels instead ( Sep 2019 news). Several lines of evidence implicate microglia in both the construction and control of Aβ plaques. “On one hand, microglia restrain the spread of Aβ plaques by surrounding and phagocytosing existing Aβ plaques on the other hand, microglia facilitate the generation of new Aβ plaques by carrying phagocytosed Aβ seeds and releasing them elsewhere,” they wrote. Louis, in a commentary that accompanied the paper. “These results suggest two-faced behavior of microglia,” wrote Yun Chen and Marco Colonna, Washington University School of Medicine in St. Microglia also delivered Aβ to the scene of a laser-induced lesion.Ablating microglia, or disabling them, slowed plaque growth in the graft.In 5xFAD mice, host microglia delivered Aβ into a wild-type neuron graft.