Related Experiment Video
Updated: Jun 30, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Purinergic Receptor P2Y12-Mediated Tau Internalization in Microglia
Hariharakrishnan Chidambaram1,2, Smita Eknath Desale1,2, Subashchandrabose Chinnathambi3,4,5
1Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune, India.
Abstract:
Microglia are the resident brain macrophage cells that are involved in constant surveillance of brain microenvironment. In Alzheimer's disease, microglia get over activated upon the accumulation of Tau and amyloid-β species in the extracellular space, ultimately leading to neurodegeneration. Microglia phagocytose the extracellular Tau species by several mechanisms among which P2Y12 receptor-mediated internalization of extracellular Tau is recently studied. Extracellular Tau activates microglia and directly interacts with the P2Y12 receptor. Tau-receptor complex is then internalized followed by perinuclear accumulation and lysosomal degradation. Upon microglial activation by extracellular Tau, P2Y12 receptor is also involved in membrane-associated actin remodeling which has its key role in active migration and phagocytosis.
Insights
Microglia, the brain's immune cells, become overactive in Alzheimer's disease. The P2Y12 receptor on microglia mediates the uptake and degradation of toxic Tau species, a key process in neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are crucial for brain surveillance and function as resident macrophages.
- In Alzheimer's disease (AD), microglia become dysregulated due to amyloid-β and Tau accumulation, contributing to neurodegeneration.
- Extracellular Tau species are implicated in microglial activation and AD pathogenesis.
Purpose of the Study:
- To investigate the role of the P2Y12 receptor in microglial uptake of extracellular Tau.
- To elucidate the mechanism of P2Y12 receptor-mediated Tau internalization and degradation.
- To understand how P2Y12 receptor signaling influences microglial responses to Tau.
Main Methods:
- Utilized cell culture models of microglia and Tau pathology.
- Investigated P2Y12 receptor expression and localization upon Tau exposure.
- Employed techniques to track Tau internalization, intracellular trafficking, and degradation.
- Analyzed P2Y12 receptor's role in actin remodeling and microglial migration.
Main Results:
- Extracellular Tau directly activates microglia via interaction with the P2Y12 receptor.
- The Tau-P2Y12 receptor complex undergoes internalization and subsequent lysosomal degradation.
- P2Y12 receptor signaling is involved in actin remodeling, essential for microglial migration and phagocytosis.
- This mechanism highlights a specific pathway for microglia to clear extracellular Tau.
Conclusions:
- P2Y12 receptor-mediated internalization is a significant mechanism for microglia to phagocytose extracellular Tau.
- Targeting the P2Y12 receptor pathway could offer therapeutic strategies for Alzheimer's disease by modulating microglial responses to Tau.
