Young microglia restore amyloid plaque clearance of aged microglia
Open accessAbstract
Alzheimer's 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 ex vivo 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 ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.
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Activation of microglial cells by inflammatory molecules has been shown to enhance Aβ clearance by microglia.
“Strikingly, activation of microglial cells by inflammatory molecules has been shown to enhance Aβ clearance by microglia [3, 26, 27].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [26]
Young microglia can restore defects in Aβ clearance in aged microglia, where aged microglia exposed to conditioned media from young microglia or GM-CSF treatment reduce amyloid plaque size in a mouse model ex vivo.
“Other studies have also shown that young microglia can restore defects in Aβ clearance in aged microglia, where aged microglia exposed to conditioned media from young microglia, or granulocyte-macrophage colony-stimulating factor treatment could reduce amyloid plaque size in a mouse model ex vivo [524].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [524]
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- Authors
- Daria, A., Colombo, A., Llovera, G., Hampel, H., Willem, M., Liesz, A., Haass, C., & Tahirovic, S.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- German Center for Neurodegenerative Diseases (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- Munich Cluster for Systems Neurology (DE)
- Corresponding author
- Haass, Christian
- Venue
- The EMBO Journal
- Published
- 2016-12-21
- Volume
- 36
- Issue
- 5
- Pages
- 583-603
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5331757
- OpenAlex
- W2565129117
- Cited by
- 174
- References
- 139
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 32 · 2023: 17 · 2022: 31 · 2021: 16 · 2020: 16 · 2019: 19 · 2018: 12 · 2017: 14
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- Funders
- European Research Council (321366)
- Excellence Cluster for Systems Neurology
- DFG (LI2534/1‐1)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- Alzheimer's disease, microglia, amyloid plaque clearance, microglial phagocytosis, APP/PS1 mice, organotypic brain slices, co-culture model, GM-CSF, microglial proliferation, neuroinflammation, ex vivo model
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Organ Culture Techniques, Culture Media, Conditioned, Microglia, Coculture Techniques, Cell Proliferation, Mice, Plaque, Amyloid
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