Immune Pruning

A new discovery on the mechanism by which the brain reduces its number of neural connections could lead to the first effective cure for Alzheimer’s and other neurodegenerative diseases like schizophrenia. The information about this discovery was presented by Dr. Beth Stevens in her lecture at the Broad Institute one June 8, 2015.

The brain is an enormous machine. It contains about 100 billion neurons, and each of these neurons has thousands of synapses, which are connections to other neurons.

These synapses are the part of the neuron where communication takes place.

Estimates of how many synapses are in the brain range from 100 trillion to 1 quadrillion -- each transferring information from one neuron to the next. In comparison, a modern computer has at most only a few billion transistors.

It is very important that these synapses are wired correctly and have the right quantity for this to happen. For a human to function properly signals have to travel along the correct pathways in the brain. These synapses are not always there however, and are selected during development. Babies are born with very few synapses but with a lot of neurons, but by around age 8 they have an extremely high number of synapses, and interconnected brains. The number of synapses then declines significantly by age 14.

Why are 8 year olds not the smartest then? It’s because the synapses are not necessarily in the right places. To deal with this, the brain prunes away synapses that are wrong or not being used. For example, young mice have synaptic connections between each of their eyes and the each visual cortex on either half of their brain. When they mature, however, the excess connections are pruned away, and each eye is connected only to its corresponding visual cortex rather than both. This seems like a reasonable thing for the brain to do, but how is it done?

The mechanisms of synaptic pruning were not well understood, but recent research has

Immune Pruning uncovered that, surprisingly, the immune system mediates a significant amount of the removal of synapses. To understand how this works, we have to understand that the brain is not just made of neurons. Each neuron is supported by many glial cells, which guide neuron growth and protect them from damage. There is more glia in the brain than there are neurons.

The recent discovery is that a certain type of glial cell, called microglia, is what prunes away unwanted synapses. These synapses are tagged by a signaling molecule called complement (comp) when they are found to be unwanted, and then the microglia converge on the synapse and eat it up. This is one of the main mechanisms by which synapses are pruned in developing brains. Microglia is actually part of the immune system.

This process can get in the way, however, as shown by Alzheimer’s disease. When there is a buildup of plaque and various debris in the brain, such as the protein amyloid beta, the debris is tagged using comp, and then the microglia converge on the debris and eat it up. The problem is, there is so much debris and so much is being eaten by the microglia that a significant portion of the synapses in the brain end up being eaten accidentally by the microglia. This loss of synapses is the main marker of the severity of

Alzheimer’s and correlates to the negative symptoms of it, like extreme memory loss and debilitating cognitive decline.

This knowledge is important for the developments of treatments for Alzheimer’s. When complement signaling is disabled it is impossible for the microglia to eat up the debris, which spares the surrounding synapses. Disabling comp signaling for this purpose could lead to the symptoms of Alzheimer’s being reduced or removed completely. The next step for curing Alzheimer’s is to develop drugs that interact with the complement receptors on microglia, preventing them from eating our brains alive, and preventing the disease progression. With drugs based off this new knowledge, Alzheimer’s disease could be an inconvenience to the brain, instead of a death sentence.

The discovery of the role of the immune system in the pruning of synapses by the use of complement signaling and microglia is a very important finding. Women are more likely to be diagnosed with Alzheimer’s than breast cancer in their lifetime. With this new knowledge, an entire new class of Alzheimer’s drugs can be developed. These drugs have much higher potential than current ones because they attack Alzheimer’s at its root cause. Still, more research must be done, but this discovery brings great hope for a real cure for Alzheimer’s and other neurodegenerative diseases.

You can view more of Dr. Stevens’ work at http://stevenslab.org/.