Another mechanism of damage involving microglia


If a nerve cannot talk to another nerve, problems may occur. Loss of myelin will slow nerve transmission but if there is no synapse (the point where one nerve contacts another nerve) there is no nerve signal transmission. In this study they look at the visual system and they find that synapses are lost, even if there is seemingly no demyelination, They showed that microglia are removing the synapses after they are programmed to be eaten by the deposition of a protein called complement. This is because microglia have complement receptors. When they blocked microglial targeting of the synapse. This was associated with less loss of function.

Now the easy thing to say is let’s block this, but it may not all be good news. It is possible that loss of a synapse may protect the nerve from too much excitation that would otherwise cause nerve damage. The other issue is to what extent blocking this pathway could be detrimental. Every day we make new synapses as we make new memories, but each night we have to forget a lot of stuff so we can make new memories for the day. Synapses need to be cleared and microglia are no doubt involved in this. So how we target the unwanted synapse stripping from the everyday synapse removal will be a therapeutic problem

Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease. Werneburg S, Jung J, Kunjamma RB, Ha SK, Luciano NJ, Willis CM, Gao G, Biscola NP, Havton LA, Crocker SJ, Popko B, Reich DS, Schafer DP. Immunity. 2019 Dec 23. pii: S1074-7613(19)30523-0.

Read the paper (if there is a pay wall)

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using post-mortem human MS tissue, a preclinical non-human primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system. Similar to other neurodegenerative diseases, microglial synaptic engulfment and profound synapse loss were observed. In mice, synapse loss occurred independently of local demyelination and neuronal degeneration but coincided with gliosis and increased complement component C3, but not C1q, at synapses. Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreased microglial engulfment of synapses and protected visual function. These results indicate that microglia eliminate synapses through the alternative complement cascade in demyelinating disease and identify a strategy to prevent synapse loss that may be broadly applicable to other neurodegenerative diseases.

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  • Stupid question probably but what produces an increased level of complement component C3 that attaches to synapses and is attacked/engulfed by microglia?

  • The night gardeners: Immune cells rewire, repair brain while we sleep

    Microglia serve as the brain’s first responders, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up debris from dead cell tissue. It is only recently that Majewska and others have shown that these cells also play an important role in plasticity, the ongoing process by which the complex networks and connections between neurons are wired and rewired during development and to support learning, memory, cognition, and motor function.

    In previous studies, Majewska’s lab has shown how microglia interact with synapses, the juncture where the axons of one neuron connects and communicates with its neighbors. The microglia help maintain the health and function of the synapses and prune connections between nerve cells when they are no longer necessary for brain function.

    The current study points to the role of norepinephrine, a neurotransmitter that signals arousal and stress in the central nervous system. This chemical is present in low levels in the brain while we sleep, but when production ramps up it arouses our nerve cells, causing us to wake up and become alert. The study showed that norepinephrine also acts on a specific receptor, the beta2 adrenergic receptor, which is expressed at high levels in microglia. When this chemical is present in the brain, the microglia slip into a sort of hibernation.

    The study, which employed an advanced imaging technology that allows researchers to observe activity in the living brain, showed that when mice were exposed to high levels of norepinephrine, the microglia became inactive and were unable to respond to local injuries and pulled back from their role in rewiring brain networks.

    “This work suggests that the enhanced remodeling of neural circuits and repair of lesions during sleep may be mediated in part by the ability of microglia to dynamically interact with the brain,” said Rianne Stowell, Ph.D. a postdoctoral associate at URMC and first author of the paper. “Altogether, this research also shows that microglia are exquisitely sensitive to signals that modulate brain function and that microglial dynamics and functions are modulated by the behavioral state of the animal.”

  • CD47: the ‘yin’ to complement’s ‘yang’?

    To model synapse development and pruning in the brain, Stevens and colleagues tapped a time-tested model of synapse refinement: the developing visual system.

    They found that during the time when synapse pruning in the visual system is at its peak, CD47 is enriched in the developing visual thalamus and localized to synapses. They also found that mice lacking CD47 (through a genetic deletion) had increased pruning activity by microglia and fewer synapses than normal mice, having lost the “don’t eat me” signal.

    The findings add fuel to the idea that the brain has a balance of opposing factors that help fine-tune its connections—a yin/yang of sorts.

    “The study is exciting because it suggests a possible cooperative interaction between ‘eat me’ and ‘don’t eat me’ signals that instruct microglia what to do when they see a synapse,” says Stevens. “As we start to delvedeeper and identify new molecules and mechanisms by which microglia are pruning, it’s important to think how all these things fit together. It’s not one pathway, but a coordinated effort.”

    Previous work in the Stevens lab showed that microglia, when given the choice, preferentially eat synapses from less active neurons compared to more active neurons. However, how microglia can tell these synapses apart remained unknown. The new study finds that in response to changes in neuronal activity, CD47 localization changes—with CD47 preferentially localized to synapses from the more active neurons. In the absence of CD47, microglia appear unable to distinguish different activity levels, as they no longer prefer to eat synapses from less active neurons.

    “We think this is the first example of a molecule regulated by neuronal activity that can put the brakes on microglial engulfment,” says Stevens. “Exploring the mechanisms underlying this and determining whether it applies more generally to synaptic refinement in other brain regions will be an important aspect of future study.”

    Preventing pruning?

    Though it’s still too soon to say, the study could have also implications for understanding and treating brain disorders. A number of neurodegenerative diseases such as Alzheimer’s disease and schizophrenia involve synapse loss, possibly through aberrant activation of pruning.

    “Whether we can leverage this protective ‘don’t eat me’ signal to curb pathological synapse loss in disease is an open question,” says Daniel Wilton, Ph.D., second author on the Neuron paper.

    Synapse ‘protection’ signal found; helps to refine brain circuits

By MouseDoctor



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