Microglia, the cells that protect the brain, are tightly regulated to not overreact. What happens when these regulatory mechanisms get out of hand?

Microglia are the cells that comprise the brain’s immune system. Under normal circumstances, they perform routine maintenance that is vital for brain function, but when pathogens are present, they enhance their pathogen ingestion and production of molecules and receptors for communication with other cells. This transition may inflict damage on healthy tissues – an irreversible process when it comes to the brain, since neurons usually do not regenerate. A recent review paper by Michal Schwartz and Ido Amit from the Weizmann Institute of Science reveals that the regulatory mechanisms that restrain this damage are more complex than previously thought.  

One of the regulatory mechanisms of immune activity in the brain is the nervous system’s isolation from the circulatory system: in addition to the blood-brain barrier, which limits the entrance of immune cells to the brain, there is also a barrier that isolates the cerebrospinal fluid from the blood, along with another barrier in the meninges. All of these ensure that the central nervous system generally contains only a small number of white blood cells that can stimulate the brain’s immune system. But when these barriers are broken – in the event of a stroke, bleeding, or autoimmune diseases, for instance – the microglia respond with force, thereby exacerbating the disease.

Another mechanism involves control over gene expression in microglia. This type of control depends on the molecule TGFβ, which serves as a means of communication between the immune system and other systems. Mice lacking this molecule display impaired gene expression in their microglia during immune response, along with neuronal death, a decline in the flexibility of the junctions between neurons (synapses), as well as motor dysfunctions

Neuronal growth factors and neurotransmitters can also regulate the immune response. For instance, when the receptors for the neurotransmitters GABA, adrenaline, and acetyl choline are activated, they inhibit the immune response

When regulation goes awry

In elderly people, or in those suffering from a neurodegenerative disease, some of the microglial regulatory mechanisms get out of balance. This disruption accelerates the rate of synapse disappearance, while at the same time decreasing the ingestion of the toxic protein clusters that it creates, therefore leading to the accumulation of toxins. This, in turn, is one of the hallmarks of neurodegenerative diseases that is manifested in a decline in cognitive function. The reason for the dysregulated microglial activity is unclear; one explanation is that old neurons secrete fewer proteins capable of inhibiting the brain’s immune system.

When there is brain damage, microglial regulation may make it difficult for the brain’s immune system cells to cope with the damage. According to one hypothesis, until microglia “get used to” the diseased state and decrease their regulatory mechanisms, it is already too late to repair the damage already inflicted on the nervous system. One solution for this is blocking these regulatory mechanisms at early disease stages, or alternatively, exposing the immune system to a stimulus that would sufficiently stimulate it to overcome them.

One of the stimuli that can be used for this purpose is LPS – a component of the outer membrane of certain bacterial strains. When used for immune system stimulation, it is able to replenish the ability of microglia to ingest amyloids – clusters of toxic proteins that appear in Alzheimer’s disease patients.

In contrast, it seems that the influence of silencing the gene CX3CR1, which inhibits microglial activity, depends on the stage of disease progression. In a 2016 study on genetically engineered mice that had this gene removed from their cells, the mice displayed an improvement in motor abilities following head injury, but only during the first days after the injury. However, when examined again one month later, their motor functions were much worse than normal mice. A similar pattern of short-term improvement with long-term worsening was also apparent when the extent of brain tissue damage was examined. So it seems that immune response activation is beneficial during the first stages following head injury, but can be deleterious during later stages.

In a recently published study in Cell journal, Michal Schwartz and Ido Amit characterized different cell populations of the brain immune system of mice with Alzheimer's disease according to differences in the genes expressed by each cell type. This analysis led to the discovery of a new and relatively rare type of microglia. Termed “Disease-Associated Microglia,” these cells have lower levels of expression of the CX3CR1 gene, and they also contain amyloid fragments, so it seems they are capable of ingesting amyloids and perhaps even impede neurodegeneration.

It therefore appears that the question whether inhibition of microglial regulatory mechanisms is beneficial or deleterious to patients depends not only on the timing of this inhibition, but also on the specific microglial population regulated. These are two examples for how a better and deeper understanding of microglial regulatory checkpoints could assist in finding more efficient drugs for neurodegenerative diseases in the future.

 

Translated by Elee Shimshoni

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