Longevity Briefs: Could We Treat Dementia By Switching The Brain’s Immune Cells To Repair Mode?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Scientists are still trying to figure out exactly what causes neurodegenerative diseases like Alzheimer’s disease to occur in the brains of some people, but it’s likely that inflammation plays a key role. Inflammation is a part of the immune system that exists to hinder the progression of infections, but causes damage to surrounding tissues when it gets out of control or lasts longer than it should. In the brain, the cells responsible for controlling inflammation and repairing damage are called microglia.

Up to 15% of cells in the brain are microglia, and they constantly surveil the brain in search of damaged neurons, pathogens and harmful proteins like misfolded amyloid, which they are able to remove. Microglia can switch between two archetypes termed M1 and M2. At one end of the spectrum, M1 microglia increase inflammation in the brain by releasing inflammatory molecules. At the other extreme, M2 microglia decrease inflammation in the brain by releasing anti-inflammatory molecules, and can initiate the repair of any damaged tissue. Microglia can exist anywhere on a continuum between M1 and M2.

In many neurodegenerative diseases, M1-type microglia seem to drive inflammation in the brain. Might it be possible to treat neurodegenerative diseases by encouraging these microglia to drift back toward the M2 ‘repair mode’?

What did the researchers do: In this article, researchers review what we know so far about the role of microglia in neurodegenerative diseases, how scientists have attempted to target microglia in the past, and what new approaches could be taken in the future.

Key takeaway(s) from this research: Previous attempts to treat or prevent neurodegenerative disease using anti-inflammatory drugs, including those that inhibit M1 microglia, have been entirely unsuccessful. Encouraging microglia to instead switch from M1 towards M2 might be a more effective approach, but so far hasn’t been properly tested in humans.

While scientists don’t know exactly how microglia control their polarisation towards M1 or M2, they do know of some mechanisms that could be targeted to promote M2 microglia. Experiments (primarily in cultured cells) have identified surface receptors and transcription factors (molecules that control the expression of genes) that are involved in encouraging microglia to become M2. There are even some existing drugs such as simvastatin (taken to lower cholesterol) and fasudil (which dilates blood vessels) that appear to promote M2 microglia. The big question, of course, is whether microglia in the brain of a living human will respond in the same way to such treatments as mouse cells.