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Published on: February 5, 2018
CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis
Zhiqiang Liu1, Carlo Condello, Aaron Schain
1Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Abstract:
In Alzheimer's disease (AD), amyloid-β (Aβ) deposits are frequently surrounded by activated microglia but the precise role of these cells in disease progression remains unclear. The chemokine receptor CX3CR1 is selectively expressed in microglia and is thought to modulate their activity. To study the specific effects of microglia activation on amyloid pathology in vivo, we crossbred mice lacking CX3CR1 with the Alzheimer's mouse model CRND8. Surprisingly, we found that CX3CR1-deficient mice had lower brain levels of Aβ40 and Aβ42 and reduced amyloid deposits. Quantification of Aβ within microglia and time-lapse two-photon microscopy in live mice revealed that these cells were highly effective at the uptake of protofibrillar amyloid but were incapable of phagocytosis of fibrillar congophilic Aβ. CX3CR1 deletion was associated with increased phagocytic ability, which led to greater amyloid content within microglial phagolysosomes. Furthermore, CX3CR1-deficient mice had an increased number of microglia around individual plaques because of higher proliferative rates, which likely contributed to an overall greater phagocytic capacity. CX3CR1 deletion did not affect the degree of neuronal or synaptic damage around plaques despite increased microglia density. Our results demonstrate that microglia can regulate brain Aβ levels and plaque deposition via selective protofibrillar Aβ phagocytosis. Modulation of microglia activity and proliferation by CX3CR1 signaling may represent a therapeutic strategy for AD.
Insights
Microglia, immune cells in the brain, clear amyloid-beta deposits in Alzheimer's disease (AD) by engulfing early-stage amyloid. Deleting CX3CR1 enhances this clearance, reducing amyloid burden and offering a potential therapeutic target for AD.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques, often surrounded by activated microglia.
- The role of microglia in AD pathogenesis is complex and not fully understood.
- CX3CR1 is a chemokine receptor primarily expressed on microglia, influencing their function.
Purpose of the Study:
- To investigate the in vivo effects of CX3CR1 deficiency on amyloid pathology in a mouse model of Alzheimer's disease.
- To elucidate the mechanisms by which microglia interact with and clear amyloid-beta deposits.
Main Methods:
- Crossbreeding CX3CR1-deficient mice with the CRND8 Alzheimer's disease mouse model.
- Quantification of brain Aβ levels (Aβ40 and Aβ42).
- Time-lapse two-photon microscopy in live mice to observe microglial-amyloid interactions.
- Analysis of microglial phagocytic activity and proliferation rates.
Main Results:
- CX3CR1-deficient mice exhibited significantly lower brain Aβ levels and reduced amyloid deposits.
- Microglia efficiently phagocytosed protofibrillar Aβ but not fibrillar congophilic Aβ.
- CX3CR1 deletion enhanced microglial phagocytic capacity and increased microglial proliferation around plaques.
- Neuronal and synaptic damage remained unaffected despite increased microglia density.
Conclusions:
- Microglia play a crucial role in regulating brain Aβ levels through selective phagocytosis of protofibrillar Aβ.
- Modulating CX3CR1 signaling impacts microglial activity and proliferation, influencing amyloid deposition.
- Targeting CX3CR1 signaling represents a potential therapeutic strategy for Alzheimer's disease.
