Stopping the aged brain from eating itself

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 [1], which affects 50% of people over 60 years old, causing reduced well-being, mental function, and economic activity [2]. 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 [3, 4]. Microglial phagocytosis is regulated by several factors, including the microglial P2Y₆ receptor (P2Y₆R) activated by extracellular UDP (uridine diphosphate) [5, 6]. We recently reported that microglial phagocytosis of synapses during aging is mediated by P2Y₆R [7]. 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 [7]. Thus, inhibiting P2Y₆R can reduce the loss of synapses and memory with age in mice, probably by preventing microglial phagocytosis of synapses (Figure 1).

Neurons in the aged brain commonly contain aggregates of the protein tau, referred to as ‘primary age-related tauopathy’ (PART), and we have previously reported that transgenic mice with neuronal tauopathy (P301S MAPT mice) had neuronal loss and memory deficits that were reduced by crossing with P2Y₆R knockout mice [8]. Tauopathy is particularly important in Alzheimer’s disease, which is also characterized by extracellular aggregates of the protein amyloid beta (Aβ) and extensive loss of neurons and memory. We found that P2Y₆R knockout prevented Aβ-induced microglial phagocytosis of neurons and reduced Aβ-induced memory loss in mice [8]. P2Y₆R knockout or inhibition also prevented neuronal loss induced by the inflammatory stimulus lipopolysaccharide [6, 9], relevant to aging because brain inflammation increases with age [4]. Brain seizures also increase in the aged, as a result of multiple pathologies, and it was recently shown that brain-seizure-induced loss of neurons and memory was reduced in P2Y₆R knockout mice as a result of reduced microglial phagocytosis of neurons [10]. Thus, P2Y₆R-dependent microglial phagocytosis may contribute to the pathology of Alzheimer’s disease, neuroinflammation and seizures, as well as normal aging.

Microglial phagocytosis of synapses also occurs during development, but in this case is beneficial by shaping neuronal networks according to experience. We found that young P2Y₆R knockout mice had reduced microglial phagocytosis of synapses and reduced memory [11], indicating that P2Y₆R contributes to microglial phagocytosis of synapses during development. It is unclear whether P2Y₆R affects memory in the ‘healthy’ adult, but P2Y₆R knockout mice retain memory better with age [7].

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 Aβ 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 [4], 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 [3, 4]. UDP activation of P2Y₆R induces the engulfment phase of microglial phagocytosis [5], and expression of the receptor is increased by inflammation, while excitation of neurons and stress of other cells induces UDP release [5, 10].

Overall, we know that P2Y₆R regulates microglial phagocytosis and this can contribute to the loss of synapses, neurons, and memory with age and age-related pathologies in mice. We do not know whether P2Y₆R does the same in humans and whether inhibition of P2Y₆R can reverse age-associated memory loss, but it would be important to find out.