Could it be that microglia build plaques rather than bust them? In the April 15 Nature Immunology, researchers led by Greg Lemke at the Salk Institute for Biological Studies, La Jolla, California, add to the evidence for this idea. In a mouse model of amyloidosis, the researchers hobbled microglial phagocytosis by deleting the two primary receptors for this process, Axl and Mer. Surprisingly, fewer dense-core plaques formed. Instead, the Aβ accumulated in wispy cotton-wool plaques and around blood vessels. The data imply that microglia normally act like trash compactors, taking up amyloid and condensing it inside lysosomes before re-depositing it in an inert form. “We conclude that dense-core plaques don’t form spontaneously; they’re constructed by microglia,” Lemke told Alzforum. He believes this may be a mechanism the brain uses to limit the damage from Aβ by confining it.
- When microglia cannot phagocytose, fewer dense plaques form in mice.
- Instead, amyloid accumulates in wispy deposits and lines blood vessels.
- Microglia may help contain amyloid by sequestering it into dense-core plaques.
The findings generated enthusiasm. “This is a landmark study,” Wei Cao, Manasee Gedam, and Hui Zheng at Baylor College of Medicine, Houston, wrote to Alzforum (full comment below). “The model the authors put forward is provocative, and it challenges our current understanding of microglia and plaque interaction.”
“The caliber of the work is terrific,” wrote Gary Landreth at Indiana University School of Medicine in Indianapolis (comment below). Henrik Zetterberg at the University of Gothenburg, Sweden, called the implications profound. “It’s an extremely exciting story, and really unexpected. It revises the amyloid cascade hypothesis, because it looks like microglia are the catalyst,” Zetterberg told Alzforum.