Journal
EMBO JOURNAL
Volume 36, Issue 5, Pages 583-603Publisher
WILEY
DOI: 10.15252/embj.201694591
Keywords
Alzheimer's disease; amyloid plaque clearance; microglia; neurodegeneration
Categories
Funding
- European Research Council under the European Union's Seventh Framework Program (FP7)/ERC Grant [321366-Amyloid]
- Excellence Cluster for Systems Neurology (SyNergy)
- German Research Foundation (DFG) [LI2534/1-1]
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Alzheimers disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel exvivo model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel exvivo model provides a valuable system for identification, screening, and testing ofcompounds aimed to therapeutically reinforce microglial phagocytosis.
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