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Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Microglia degrade Alzheimer's amyloid-beta deposits extracellularly via digestive exophagy
Rudy G Jacquet1, Fernando González Ibáñez2, Katherine Picard2
1Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
Abstract:
How microglia digest Alzheimer's fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in structures resembling lysosomal synapses. Signaling studies demonstrate that the PI3K-AKT pathway modulates the formation of lysosomal synapses, as inhibition of PI3K1β or AKT1/2 reduces both lysosome exocytosis and actin polymerization, both required for the formation of the compartments. Finally, we show that small fibrils of Aβ previously internalized and trafficked to lysosomes are exocytosed toward large Aβ aggregates by microglia. Thus, the release of lysosomal contents during digestive exophagy may also contribute to the spread and growth of fibrillar Aβ.
Insights
Microglia digest large amyloid-beta plaques via digestive exophagy, releasing enzymes into extracellular compartments. This process, modulated by the PI3K-AKT pathway, may paradoxically contribute to plaque growth.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease is characterized by amyloid-beta (Aβ) plaques.
- The mechanism by which microglia digest large, fibrillar Aβ plaques is poorly understood.
- Phagocytosis is insufficient for clearing large Aβ aggregates.
Purpose of the Study:
- To elucidate the mechanism of microglial digestion of large amyloid-beta plaques.
- To investigate the role of extracellular compartments and lysosomal enzymes in Aβ degradation.
- To identify signaling pathways regulating this process.
Main Methods:
- Primary microglial cell cultures and model Aβ plaques.
- Transmission electron microscopy in 5xFAD mouse brains.
- Signaling pathway inhibition (PI3K-AKT pathway).
- Analysis of lysosome exocytosis and actin polymerization.
Main Results:
- Microglia form acidic extracellular compartments, termed lysosomal synapses, to digest Aβ plaques.
- Digestive exophagy, involving exocytosis of lysosomal enzymes like acid phosphatase, was confirmed in vivo.
- The PI3K-AKT pathway regulates lysosomal synapse formation by controlling lysosome exocytosis and actin polymerization.
- Microglia exocytose internalized Aβ fibrils towards larger aggregates, potentially promoting plaque growth.
Conclusions:
- Microglia employ digestive exophagy to degrade large amyloid-beta plaques.
- The PI3K-AKT pathway is a key regulator of this microglial degradative process.
- Digestive exophagy may contribute to the spread and growth of fibrillar Aβ in Alzheimer's disease.
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