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Updated: Aug 4, 2026
An Engulfment Assay: A Protocol to Assess Interactions Between CNS Phagocytes and Neurons
Published on: June 8, 2014
P2Y6 receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging
Jacob M Dundee1, Mar Puigdellívol1,2, Richard Butler3
1Department of Biochemistry, University of Cambridge, Cambridge, UK.
Abstract:
Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y6 receptor (P2Y6 R) on the surface of microglia, inducing microglial phagocytosis of neurons. However, whether the activation of P2Y6 R affects microglial phagocytosis of synapses is unknown. We show here that inactivation of P2Y6 R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal-glial co-cultures. In vivo, wild-type mice aged from 4 to 17 months exhibited reduced synaptic density in cortical and hippocampal regions, which correlated with increased internalization of synaptic material within microglia. However, this aging-induced synaptic loss and internalization were absent in P2Y6 R knockout mice, and these mice also lacked any aging-induced memory loss. Thus, P2Y6 R appears to mediate aging-induced loss of synapses and memory by increasing microglial phagocytosis of synapses. Consequently, blocking P2Y6 R has the potential to prevent age-associated memory impairment.
Insights
Blocking the P2Y6 receptor (P2Y6 R) in aging brains reduces microglial phagocytosis of synapses, preventing synaptic and memory loss. This finding offers a potential therapeutic target for age-associated memory impairment.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Aging leads to synaptic and memory loss, with microglial phagocytosis implicated.
- Microglial P2Y6 receptor (P2Y6 R) activation by UDP can induce neuronal phagocytosis.
- The role of P2Y6 R in microglial synapse phagocytosis during aging is unclear.
Purpose of the Study:
- To investigate the role of P2Y6 R in microglial phagocytosis of synapses during aging.
- To determine if P2Y6 R mediates age-related synaptic and memory decline.
Main Methods:
- In vitro studies using neuronal-glial co-cultures and isolated synapses (synaptosomes).
- In vivo studies using wild-type and P2Y6 R knockout mice aged 4-17 months.
- Assessment of synaptic density, microglial phagocytosis of synaptic material, and memory function.
Main Results:
- Inactivation of P2Y6 R reduced microglial phagocytosis of synaptosomes and synaptic loss in co-cultures.
- Aging wild-type mice showed decreased synaptic density and increased microglial synaptic material uptake.
- P2Y6 R knockout mice lacked aging-induced synaptic loss, microglial uptake, and memory impairment.
Conclusions:
- P2Y6 R activation promotes microglial phagocytosis of synapses.
- P2Y6 R mediates age-associated synaptic and memory loss.
- Blocking P2Y6 R is a potential strategy to prevent age-related memory decline.
