P2Y6R Inhibition as a Strategy to Reduce Age-Related Memory Loss

Memory is in some way encoded in the synaptic connections between neurons, with the precise details yet to be determined. Destruction of synapses is a characteristic of neurodegenerative conditions involving loss of memory. Researchers here identify a regulatory receptor that controls the removal of synapses by the innate immune cells known as microglia in the brains of mice. Blocking the activity of this receptor reduces age-related memory loss in mice, suggesting that this aspect of aging is largely a matter of inappropriate microglial activity, destroying synapses that should remain intact.

Removal of synapses is not a bad thing per se, and is thought to be a necessary part of neural plasticity, essential for memory and learning. A range of evidence suggests that excessive synaptic removal might take place in an aged brain, however. This may be driven by chronic inflammation, a state the provokes microglia into excessive activity, but this is by no means certain. There is much yet to explore regarding the underlying mechanisms.

P2Y6 receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging

Microglia are central nervous system macrophages, specialized in the phagocytosis (i.e., engulfment and degradation) of bacteria, synapses, neurons, debris, and aggregated proteins. Microglia can phagocytose synapses during development, neuropathology, and aging, and microglia can also phagocytose dendrites, axons, and intact neurons. Microglial phagocytosis of neuronal structures is mediated by eat-me signals, opsonins, and phagocytic receptors. Interestingly, it has been shown that genetic knockout of the opsonin C3 reduced aging-induced loss of hippocampal synapses, neurons, and memory; and similarly, knockout of the phagocytic receptor TREM2 reduced aging-induced hippocampal synaptic and neuronal loss in mice. Thus, one may hypothesize that the neuroinflammation accompanying aging drives microglial phagocytosis of synapses, resulting in memory impairment and brain atrophy. Microglial biology changes with age, including upregulated expression of phagocytic receptors and opsonins, potentially resulting in excessive phagocytosis of the aging brain.

The P2Y6 receptor (P2Y6R, expressed from the P2ry6 gene) is a microglial receptor that mediates microglial phagocytosis of neurons. P2Y6R is expressed by multiple cell types in the body, but within the brain is almost exclusively expressed by microglia. Damaged or stressed neurons release the nucleotide UTP, which is rapidly degraded into UDP by extracellular nucleotide-degrading enzymes, and localized UDP then activates the P2Y6R on microglia to engulf such neurons. We have shown that activating P2Y6R causes microglia to engulf live neurons, and P2Y6R deficiency prevents lipopolysaccharide (LPS)-induced microglial phagocytosis of neurons both in vitro and in vivo. Moreover, P2Y6R knockout mice were also resistant to memory loss induced by beta-amyloid and extracellular tau. These previous studies lead us to ask whether (i) P2Y6R mediates microglial phagocytosis of synapses, and (ii) the synaptic and memory loss induced by natural aging of mice was also mediated by P2Y6R.

We found that aging wild-type mice to 17 months of age resulted in synapse and memory loss, whereas P2Y6R knockout mice had preserved memory. Microglia from 17-month-old wild-type mice had an age-associated increase in the internalization of synaptic material, but no such increase was observed in microglia from 17-month-old knockout mice. Moreover, we show here that inactivation of P2Y6R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal-glial co-cultures. These findings are significant as they support the hypothesis that microglial phagocytosis of synapses contributes to aging-induced memory loss, and, more specifically, that inhibition of the P2Y6R may prevent this memory loss.

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