Team:UCL/Background/Microglia

IMMUNE CELLS IN THE BRAIN

The Brain

The brain is composed of two types of cells: neurons and glial cells. Neurons are the workhorses of the brain, and the glial cells are the stable hands. Neurons are electrically excitable cells which convey information chemically to one another via ‘synapses’. It is within their networks that we store our memories, personalities, and cognitive and intellectual abilities. They are the fundamental unit of the nervous system and the site of information processing.

However, they are outnumbered ten to one by glial cells. Glia are supportive cells. They maintain the homeostasis of the brain environment, provide nutrients, insulate neurons and protect them. Astrocytes, oligodendrocytes, Schwann cells and microglia are all types of glia.

Microglia

Microglial cells are the endogenous immune cells of the nervous system. Unlike other glia, microglia are distributed in relatively expansive non-overlapping territories (Kreutzberg 1995) across the brain and spinal cord (the ‘central nervous system’ - CNS). They constitute almost 15% of brain glial cells. When activated, they can become ‘brain macrophages’, able to perform immunological roles. Yet, expression of immune molecules is not synonymous with neuroinflammation as these proteins can have functions specific to the central nervous system. Through their involvement in pain mechanisms, microglia also respond to external threats, for example, synaptic stability and malleability, as well as capability of removing ‘faulty parts’ at the ends of neurons (axon termini).

Microglia move across the CNS looking for damaged neurons, plaques, and foreign bodies (Gehrmann et al. 1995). The CNS is deemed ‘immune privileged’, because they are severed from the rest of the body’s immune system by the blood brain barrier, in order for the brain to maintain chemical integrity and prevent infection. In the case where an infectious organism does cross the barrier, microglia must mobilise quickly to counter the threat by inflaming the area, producing antibodies and engulfing (phagocytosing) the infectious agent. Since they do not have access to the rest of the body’s antibodies, they must be extremely sensitive towards potentially harmful agents (Dissing-Olesen et al. 2007).

Microglia are extremely plastic cells. They are, essentially, the ‘chameleons’ of neuroscience. They undergo complex structural changes based on their location and the particular function they are trying to perform (Gehrmann et al. 1995). ‘Ramified’ state microglia stay in one place and spindly. They are formed when there are no immune tasks for the microglia to conduct. Their thin processes constantly move about and survey the surrounding area, looking for cellular debris, attractant chemicals, infectious agents, etc. They are, essentially, primed to act in the brain’s defence or for maintenance (Aliosi 2001). ‘Amoeboid’ state microglia, most commonly found in the corpus callosum (the neural matter connected the two halves of the brain), are able to move through neural tissue as a scavenger, to phagocytose cellular debris. When a ramified cell receives an excitatory factor it undergoes a graded response towards its fully ‘activated’ state. The microglia thicken, retract their branches and begin to proliferate more rapidly. They may present antibodies and/or engulf their prey. Activated microglia produce a lot more inflammatory agents, chemoattractants and proteases. Proteases cleave substances in the cell’s path, such as the extracellular matrix, cellular debris and protein plaques. For example, the protease MMP-9 breaks up extracellular matrix and amyloid plaques.

Neuroinflammation caused by microglia, is, however, damaging to the neural environment, and has been suggested to cause different kinds of plaque formation and to disturb the growth of neurons branches. Sustained activation of microglia around damage sites, including plaques, can lead to cell death as chronic inflammation can prove neurotoxic (Streit 2006).

In Alzheimer’s disease (AD), microglia may help to form plaques by producing more APP, which forms amyloid when cleaved, leading to tangle formation (Hensley 2010). They are attracted to the characteristic senile amyloid plaques in AD pathology (Solito and Sastre 2012). Plaques activate microglia and make them produce inflammatory, neurotoxic agents, and proteases for plaque degradation. It would seem that they have both positive and negative effects in AD, in that they help to break down amyloid plaques and reduce the amyloid burned on the brain. These amyloids are thought to be the major driver of AD under the ‘Amyloid Hypothesis’, but especially in older brains and in the later stages of the disease, the negative effects of their neuroinflammatory functions can outweigh their benefits and speed up the course of AD. Anti-inflammatory drugs have been proven to be able to reduce the risk of AD.

Why, then, would UCL iGEM wish to use microglia as a chassis for our genetic circuit, which tries to combat AD, if microglia may contribute to it? It would appear that in late stage AD, microglia do not produce enough protease to degrade amyloid plaques. Our circuit increases the production of strong amyloid proteases, MMP-9 and neprilysin, in order to clear amyloid burden. Our microglia are also meant to produce ‘vasoactive intestinal peptide’ (VIP), which acts to de-activate microglia. Once our microglia arrive at the plaques’ vicinity, they will de-activate themselves and other native microglia, whilst still producing the necessary protease.

For more on microglia, have a look at the information here.