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Glial Cells Protect the Brain

Glia are essential for healthy brain functioning

Glial cells (glia) are essential workers and silent partners of the brain and CNS. They do all the thankless tasks that keep your brain running smoothly while neurons get all the credit. They also control many neuron behaviors.

Glia are not neural tissue. Unlike nerve cells, they do not fire action potentials or ponder the mysteries of the universe. Rather they are part of the neuroimmune system. The neuroimmune system is the brain's innate immune system (Gruol 2023). It is composed of glial cells like astrocytes and microglia.

Glia support the brain and help keep it healthy. They prune unnecessary nerve connections; optimize neuronal connections; help coordinate networking between neurons; remove debris such as dead neurons, protein buildup and beta-amyloid plaques; form myelin sheaths around nerves; and get called up to act as immune cells in an emergency.

Glia are excellent communicators and use chemical signals to talk to each other and nerve cells. They make signaling factors or cytokines called neuroimmune factors (if produced elsewhere in the body neuroimmune factors are called immune factors).

Glia mobilize when the brain is injured

Glia defense mechanisms are deployed due to brain lesions or other injury.

Glia can provide neurons with metabolic support: Injured brains need a steady supply of energy to heal. Your healthy brain uses about 25% of the glucose you eat each day so imagine how much an injured brain needs.

Astrocytes bring healing energy and nutrients: Astrocytes use glucose to produce ATP and lactate. They can directly transfer lactate and healthy mitochondria to neurons. Neurons use lactate to make energy and for signaling. The healthy mitochondria replace ill and damaged mitochondria in neurons (discussion Quincozes-Santos et al. 2021).

Astrocytes provide neurons with nutrients from blood vessels and make neurotransmitters. This helps support the blood brain barrier (BBB) integrity. Astrocytes interact with blood vessels via their endfeet. Astrocytic endfeet make up the glia limitans, a thin barrier that supports and protects the brain.

Astrocytes maintain neurotransmitters: Neurotransmitters are chemical messengers; they allow neurons and other cells to communicate. Neurotransmitters can be excitatory (increase chance that nerve will fire), inhibitory (reduce chance that nerve will fire), or modulatory (adjust the activity of other neurotransmitters).

Excitatory neurotransmitters, chemical massagers in brain grey matter which cause a nerve to fire, use most of the energy needed by the brain. The main excitatory neurotransmitter in the brain is the amino acid glutamate. It is believed that glutamate-mediated neurotransmission takes up 80% of the energy used by the brain's grey matter (discussion Bélanger et al. 2011).

Besides providing energy, astrocytes are also involved in the glutamate-glutamine cycle which maintains the two main neurotransmission chemicals; glutamate and gamma aminobutyric acid (GABA). Astrocytes convert glutamate into glutamine (Bélanger et al. 2011). Glutamine is an amino acid involved in muscle recovery, immune function, gut health, brain function, energy and more.

Glia produce healing chemicals: Glia cells release chemical factors designed to improve nerve survival, function, regeneration, differentiation, and birth (neurogenesis) (Quincozes-Santos et al. 2021).

Chemical factors that prompt nerve health and repair include brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), S100B, transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), nerve growth factor (NGF), and neurotrophins 3 and 4.

After injury, microglia can express genes that are associated with cell survival, neuroprotection, and phagocytosis (clearing cellular debris).

Glia cells can remyelination damaged neurons. Central nervous system (CNS) inflammation, injury or infection can strip myelin from neurons. Glia can prompt remyelination and recover of the injured areas.

The process of remyelination is started when oligodendrocyte progenitor cells (OPCs) are recruited and activate at the damaged site. Oligodendrocyte are a type of neuroglia that produces myelin. The OPCs proliferate, differentiate, and mature to become full grown oligodendrocytes (OLs) ready for myelin sheath formation (discussion Quan et al. 2022).

Science Bite: Are glia heros or villains?

Glia turn into complex superheroes (or is it supervillains?) when confronted with brain injuries or disease.

Brain damage causes astrocytes to undergo astrocyte reactivity (also called astrocyte activation, reactive astrogliosis, astrocytosis, reactive gliosis, astrogliosis, astrocyte re-activation, astrocyte reactivity and astrocyte reaction).

No matter what you call it, astrocytes undergo hypertrophy and proliferation due to an increase (upregulation) in glial fibrillary acidic protein (GFAP). GFAP likely plays a role in astrocyte, neuron, and cell interactions. While GFAP is associated with reactive astrocyte remodeling it is only one marker of reactive astrocytes (discussion and table in Escartin et al. 2021).

Reactive astrocytes have multiple subtypes; some are generally neurotoxic and others generally neuroprotective. These subtypes used to be called A1 and A2 but current research indicates that there are many subtypes. "Numerous mixed scenarios of malfunctional and resilient astrocytes plausibly exist, with multidirectional transitions among them." by Escartin et al. 2021.

Likewise microglia have two extreme states: M1 (causes inflammation) or M2 (reduces inflammation).

In both causes, astrocytes and microglia can develop into many intermediate forms. Also, whether any of these states is beneficial or not depends on the damage or what disease is present.

Take Home Message: Neuroimmune cells, also called glia, are similar to regular immune cells in that they play a role in healing and in disease. Glia have endless genetic variations and can transform into numerous forms readily. As a result, glia can be beneficial, detrimental or both.

References:

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