28 Nov 2021

Microglia are known to ingest Aβ plaques, but might Aβ-loaded microglia unwittingly spew their innards in otherwise healthy regions of the brain? That is the conclusion of a paper published November 22 in Nature Neuroscience. Researchers led by Melanie Meyer-Luehmann of the University of Freiburg, Germany, reported that when wild-type neurons were grafted into the brain of a 5xFAD mouse, the host’s microglia—some of which had just feasted on nearby amyloid plaques—infiltrated the foreign tissue. In so doing, they helped spur the development of Aβ plaques in the graft. While it is unclear whether, or under what conditions, microglia pull off something similar in the AD brain, the study adds to mounting evidence that microglia may help spread amyloid.

“These results suggest two-faced behavior of microglia,” wrote Yun Chen and Marco Colonna, Washington University School of Medicine in St. Louis, in a commentary that accompanied the paper.

“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.

Several lines of evidence implicate microglia in both the construction and control of Aβ plaques. 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). 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). Others have found that microglia release Aβ-containing protein complexes that seed plaques (Dec 2017 news).

First author Paolo d’Errico and colleagues investigated whether microglia promote Aβ deposition in plaque-free regions of the brain. To model this scenario, they transplanted embryonic neuronal cells from wild-type mice into young 5xFAD mice that had no amyloid plaques yet. 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). Here, too, the researchers found that plaques cropped up in the graft a month after transplant, where they grew over time.

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. Instead, the researchers observed massive infiltration of host microglia to the grafts' border regions. Small particles of Aβ were seen inside of, or closely associated with, some of the infiltrating microglia.

As plaques grew inside the grafts, more microglia rallied to surround the plaques. 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.

Microglia Deliver. In 5xFAD mice (top), microglia (green) infiltrate wild-type graft (dotted line), where Aβ plaques (red) soon emerge. In 5xFAD mice lacking Irf8 (bottom), microglia largely stay put and plaques do not grow in the graft. [Courtesy of d’Errico et al., Nature Neuroscience, 2021.]

If microglia play a role in delivering Aβ into wild-type grafts, then sapping the cells' function should stifle this activity, the researchers reasoned. They used several models to test the idea. In old 5xFAD mice, whose microglial phagocytose poorly, fewer Aβ plaques formed in the wild-type grafts. The same was true when 5xFAD hosts lacked Irf8, a gene that promotes microglial branching and motility (see image above). 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. 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. D’Errico added that none of the treatments completely inhibited or ablated microglia, either, and that residual Aβ-loaded microglia still made their way into the grafts.

Do microglia supply all of the Aβ that forms plaques within the grafts, or might other sources of the peptide contribute to plaque growth? D’Errico said that while microglia might bring in the starter material, it is possible that once stationed within the grafts, they incorporate Aβ that enters in other ways, such as by diffusion. The grafted wild-type neurons do not produce aggregation-prone Aβ, hence any plaque-forming Aβ must derive from host cells.

Microglia are known to rapidly migrate toward the site of an injury. Might they unwittingly transport Aβ in this scenario, also? Indeed, in response to a laser-induced, localized tissue injury, microglia in 5xFAD mice raced to the scene. Using in vivo two-photon microscopy to watch events unfold over time, d’Errico and colleagues found that not only did the microglia bring Aβ along with them, they also sparked the formation of Aβ plaques in the lesion (see image below). In contrast, microglia in Irf8 knockout mice did not migrate to the lesion, and no Aβ plaques formed there. Together, the findings suggested that microglia summoned to the scene of an injury, such as a graft or laser zap, can bring Aβ with them, seeding plaques.

Help or Hurt? In response to a laser-induced lesion in 5xFAD mouse brain, microglia (green) flock to the scene of the injury over 24 hours. Upon their arrival, Ab deposits form (red). [Courtesy of d’Errico et al., Nature Neuroscience, 2021.]

How likely is this scenario to unfold in the AD brain? D’Errico said that in the aged brain of a person with AD, injuries such as microbleeding or microinfarcts could potentially induce microglia to migrate from one region to another.

However, Chen and Colonna questioned whether that type of damage would be enough to entice microglia to abandon their posts around plaques. “In the natural progression of AD pathology, it is less likely that unaffected brain regions provide such strong secondary signals to induce microglial migration,” they noted. “In fact, the heavy burden of original Aβ plaques potently lures surrounding microglia, inducing their clustering that then serves as a barrier to prevent further Aβ spreading. Thus, whether and how microglia that enclose phagocytosed Aβ seeds are distracted from their original location and migrate to nonpathological regions will require further investigation,” they wrote.—Jessica Shugart

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References

News Citations

1. Are Microglia Plaque Factories? 4 Sep 2019
2. Microglia Build Plaques to Protect the Brain 21 Apr 2021
3. Barrier Function: TREM2 Helps Microglia to Compact Amyloid Plaques 28 May 2016
4. Do Microglia Spread Aβ Plaques? 21 Dec 2017
5. Aβ, Shifty Drifter? Tissue Grafting Sheds Light on Plaque Formation 3 Mar 2003

Further Reading

News

1. Wiping Out Microglia Prevents Neuritic Plaques 8 Mar 2018
2. TREM2, Microglia Dampen Dangerous Liaisons Between Aβ and Tau 1 Jul 2019