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The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases
1Department of Biochemistry, University of Cambridge, Cambridge, UK.
Abstract:
Neurodegenerative diseases are associated with chronic neuroinflammation in the brain, which can result in microglial phagocytosis of live synapses and neurons that may contribute to cognitive deficits and neuronal loss. The microglial P2Y6 receptor (P2Y6R) is a G-protein coupled receptor, which stimulates microglial phagocytosis when activated by extracellular uridine diphosphate, released by stressed neurons. Knockout or inhibition of P2Y6R can prevent neuronal loss in mouse models of Alzheimer's disease (AD), Parkinson's disease, epilepsy, neuroinflammation and aging, and prevent cognitive deficits in models of AD, epilepsy and aging. This review summarises the known roles of P2Y6R in the physiology and pathology of the brain, and its potential as a therapeutic target to prevent neurodegeneration and other brain pathologies.
Insights
Chronic neuroinflammation drives neurodegeneration. Targeting the microglial P2Y6 receptor (P2Y6R) may prevent synaptic loss and cognitive decline in brain diseases.
Area of Science:
- Neuroscience
- Neuroinflammation
- Receptor Pharmacology
Background:
- Neurodegenerative diseases involve chronic brain inflammation.
- Microglial phagocytosis of synapses and neurons contributes to cognitive deficits.
- The P2Y6 receptor (P2Y6R) on microglia mediates this phagocytosis when activated by uridine diphosphate.
Purpose of the Study:
- To review the roles of P2Y6R in brain physiology and pathology.
- To explore P2Y6R as a potential therapeutic target for neurodegenerative diseases.
Main Methods:
- Literature review of studies on P2Y6R in the brain.
- Analysis of P2Y6R function in various neurological disease models.
Main Results:
- P2Y6R activation by uridine diphosphate stimulates microglial phagocytosis.
- Inhibition or knockout of P2Y6R protects against neuronal loss and cognitive deficits in models of Alzheimer's disease, Parkinson's disease, epilepsy, and aging.
- P2Y6R plays a significant role in neuroinflammation and neurodegeneration.
Conclusions:
- P2Y6R is a key mediator of neuroinflammation and neurodegeneration.
- Targeting P2Y6R offers a promising therapeutic strategy for various brain pathologies.
- Further research into P2Y6R modulation could lead to novel treatments for cognitive decline.
