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Updated: Sep 8, 2025
Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice
Sepideh Kiani Shabestari1, Samuel Morabito2, Emma Pascal Danhash3
1Department of Neurobiology & Behavior, UC Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, UC Irvine, Irvine, CA 92697, USA.
Abstract:
Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.
Insights
Microglia play a protective role in Alzheimer's disease (AD) by preventing brain calcification and hemorrhages. Restoring microglia in AD mice reverses pathology and improves lifespan, highlighting their therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are key immune cells in the brain, implicated in Alzheimer's disease (AD) pathogenesis.
- The precise role of microglia in AD pathology and their impact on lifespan are not fully understood.
Purpose of the Study:
- To investigate the function of microglia in Alzheimer's disease using a novel microglial-deficient mouse model.
- To explore the therapeutic potential of microglia in mitigating AD-associated pathology.
Main Methods:
- Generated a CSF1R hypomorphic mouse model genetically lacking microglia to study AD.
- Administered wild-type microglia to repopulate the microglial niche in adult mice.
- Analyzed human AD tissue and induced pluripotent stem cell (iPSC)-derived microglia.
Main Results:
- Microglial deficiency shifted amyloid pathology from plaques to cerebral amyloid angiopathy (CAA), increasing brain calcification, hemorrhages, and mortality.
- Repopulation with wild-type microglia prevented these pathological changes and premature death.
- Human AD tissues and iPSC-microglia showed impaired calcium crystal phagocytosis due to TREM2 loss.
Conclusions:
- Microglia exert protective functions against CAA, blood-brain barrier dysfunction, and brain calcification in AD.
- Microglia-mediated phagocytosis of calcium crystals is crucial and can be impaired by AD risk genes like TREM2.
- These findings underscore the therapeutic potential of microglia in Alzheimer's disease treatment.
