More on P2Y6R Inhibition as a Strategy to Reduce Synaptic Loss in the Brain
Researchers recently found that inhibition of P2Y6R in microglia prevents these innate immune cells from excessively destroying synapses in the aging brain. The removal of synapses is just as important as their creation when it comes to the function of the brain, particularly memory. But with aging this removal process becomes too aggressive, for reasons yet to be fully understood. This short commentary offers a little more discussion on the topic. Work on P2Y6R inhibition remains at an early stage, some distance from compelling evidence for it to be a good basis for therapy. We shall see where it goes.
The brain shrinks with age, accompanied by a loss of synapses and memory. We outline here recent evidence in mice that this loss is due to microglial phagocytosis of the synapses, mediated by the microglial P2Y6 receptor (P2Y6R). Brain atrophy during aging appears to be partly due to brain cells, called microglia, eating bits of neurons and the connections between neurons, called synapses. Brain shrinkage and loss of synapses correlate with age-associated memory impairment.
There is evidence in mice that aging-induced loss of synapses and memory is due to the phagocytosis (i.e. eating) of synapses by microglia. Microglial phagocytosis is regulated by several factors, including the microglial P2Y6 receptor (P2Y6R) activated by extracellular UDP (uridine diphosphate). We recently reported that microglial phagocytosis of synapses during aging is mediated by P2Y6R. Inhibition or knockout of P2Y6R reduced microglial phagocytosis of synapses and synaptic loss in co-cultures of neurons and microglia. In vivo, microglial phagocytosis of synapses was increased in the brains of aged (17 months old) wild- type mice, compared to adult (4 months old) mice, but this increase was absent in P2Y6R knockout mice. P2Y6R knockout mice also had reduced aging-associated loss of synapses and memory.
What is inducing microglial phagocytosis of the brain in aging? We do not know for sure, but some factors that accumulate with age (such as amyloid-β aggregates, tau aggregates, or excess glutamate) stress neurons such that they expose so-called "eat-me" signals (such as UDP) that induce microglia to eat the neurons. Additionally, there is a general increase in inflammation within the brain with age that activates microglia and stimulates microglial phagocytosis, in part by the release of 'opsonins', such as complement factors C1q and C3, that bind to neurons and synapses, inducing microglia to phagocytose them. UDP activation of P2Y6R induces the engulfment phase of microglial phagocytosis, and expression of the receptor is increased by inflammation, while excitation of neurons and stress of other cells induces UDP release.