Microglia have been studied extensively for their role in various neurodegenerative diseases and brain injuries, including Alzheimer’s disease, Parkinson’s disease, Epilepsy, Frontal Temporal dementias, Amyotrophic Lateral Sclerosis (ALS), ischemic injury, and traumatic brain injuries (TBIs). Their activation has even been called the “hallmark” of many neurodegenerative conditions. However, whether their role is beneficial or harmful in each case is still a source of much debate.
Let’s look at how these cells play a key role in neurodegenerative disease research by focusing on one illness in particular: Alzheimer’s Disease. First, we’ll recap the basics of these important cells.
Introduction
Microglia are specialized macrophages that live in the Central Nervous System (CNS). These cells are the neighborhood watch and act as the CNS’s main immunodefense. They normally exist in what is deceptively referred to as a “resting” state but a watchful state is a far more helpful descripture: like napping cats, these ramified cells are hyper-aware of their surroundings and spring into action when they detect any disturbances in cerebral homeostasis. Also like our feline friends, each microglia has its own territory, a radius of 15–30 µm that it patrols. They hunt at speeds of up to 1.5 µm/min making them the fastest moving structures in the brain. They’re capable of collectively scanning the brain every few hours using feeler-like protrusions that grow and shrink at a rate of 2–3 µm/min. Once activated, their soma grows and they become less ramified. Depending on the nature of the stimulus that irked them, they’ll do any combination of gobbling up the offender by phagocytosis and secreting trophic and pro- or anti-inflammatory factors. As with other immune cells, this process can be helpful or harmful to the body and this duality is where the academic debate centers.
Alzheimer’s Disease
Alzheimer’s Disease (AD) is the most common progressive neurodegenerative disorder affecting the elderly population worldwide. It is characterized by increasing memory impairment over time resulting eventually in significant cognitive impairment and decreased ability of the body to maintain its vital functions. The exact cause is unknown but cerebral deposition of amyloid-beta (Aβ) aggregates or plaques and the formation of neurofibrillary tangles are thought to be core pathological hallmarks.
There is much debate over whether microglia play a more helpful or harmful role in AD and if in some cases it’s both or if it switches at different points in the disease. A 2015 review extensively details both the beneficial and harmful role microglia seem to play.
Let’s look at some of what we know so far:
Two Sides to their Nature: Like other macrophages, in vitro experiments show us that microglia will “activate” into a pro-inflammatory, pro-phagocytic M1 phenotype in response to LPS or into an anti-inflammatory, pro-growth and neurotrophic factor M2 phenotype in response to IL-6/10. In vivo however, their phenotypic characteristics may not be so demarcated as the cerebral microenvironment they live in provides a far more diverse array of stimuli that may fluctuate in their concentrations at various points in the disease. The cells themselves may also respond differently to future stimuli based on previous exposure.
Paying Attention and Not Fooled: Almost 30 years ago, electron microscopy showed us Aβ plaques intricately embraced by microglia. More recently, two-photon microscopy has allowed us to watch the microglia rapidly react to these Aβ aggregates, growing in their population size and shrinking with the size of the plaques and becoming far more phagocytic in the vicinity of these plaques.
The Bossy Blood Brain Barrier: How our microglial cells respond in AD may be largely due to triggering factors sent by the blood brain barrier (BBB) that alter the microenvironment of these cells and may play an important part in signalling how the cells should respond. It may be that minor damage to the BBB causes the release of pro-inflammatory clotting factors is what triggers initial microglial activation or even skews them towards a more proinflammatory response. This could be aggravated by the BBB’s ability to call on peripheral cells, like circulating monocytes shown to phagocytose Aβ plaques. These cells and immuno-activating factors may also enter the brain via parts of the brain ungoverned and uncovered by the BBB. Increased likelihood of failure of the integrity of the BBB as the body ages may explain why AD is more common in the elderly population.
Piggy in the Middle: A 2015 paper suggested a new significance behind heavy microglial involvement in the structures of Aβ plaques: that they were acting as a physical barrier to Aβ plaque expansion and axonal damage. This is reminiscent of the granulomas formed by lymphocytes and macrophages in latent tuberculosis (TB).
Throwing a Tantrum: Aβ plaques damage nervous tissue resulting in the secretion of microglia-activating DAMPs. They also signal the microglia by direct cell-cell receptor activation. This may induce a hyper pro-inflammatory response from the microglia resulting in further neural cell damage and further activation. This vicious cycle may further plaque development. A 2008 paper proposed that over time, frustrated phagocytosis or the failure of the microglia to engulf its target may occur once the plaques have developed in the later stages of the disease, a process that is again pro-inflammatory.
Reinforcing the Troops: Microglial cell activation has also been shown to slow down or even reverse AD. Immunization experiments thought to trigger the formation of anti-Aβ antibodies showed microglial clearance of Aβ plaques suggesting that promoting their phagocytic activity clinically may improve disease prognosis. Even immunization with the antibodies directly resulted in clearance, in part due to microglia. Two vaccines have been created, Bapineuzumab and Aducanumab to test if this holds true in humans. While Bapineuzumab failed to show merit and resulted in severe CNS inflammation in some instances, Aducanumab may be more promising. The discrepancy between these findings may be attributed to Aducanumab binding conformational epitopes on Aβ aggregates and Bapineuzumab binding linear Aβ epitopes.
Changing Battle Conditions: The phagocytic abilities of microglia may be best promoted clinically by broadly promoting the infiltration of microcyte precursor cells from the bone marrow and increase their differentiation and proliferation using M-CSF (macrophage-colony stimulating factor). Another approach would be to reduce anti-inflammatory factors that hinder phagocytosis but this too has the risk of promoting an overly enthusiastic and damaging pro-inflammatory response.
Personality Switching: A 2016 study showed success at ameliorating some symptoms of AD in an AD mouse model. They used a tyrosine kinase inhibitor (GW2580) to block colony-stimulating factor 1 receptor (CSF1R), a protein the activation of which is associated with microglial activation and a pro-inflammatory response. Blocking CSF1R switched the microglia to a more anti-inflammatory phenotypic profile and reduced their rate of proliferation. This may prove to be a new course of treatment if it moves into human clinical trials. A phase 1 clinical study conducted in 2015 by GliaCure used a small molecule drug, GC021109, to successfully switch the phenotype of microglia to a more anti-inflammatory state that was more phagocytic. Subjects in the treatment group showed a significant decrease in AD biomarkers like Aβ.
Conclusion
From the above, it is clear that microglial research is giving us exciting new potential treatment options. It is clear that they have taught and will continue to teach us a lot about how to assess and treat perhaps even prevent AD but the research still has a ways to go. One pivotal point may be that when designing new therapies, we need to account for the individual microenvironment of the CNS of each subject to understand how best to treat their disease and this would account for the conflicting results seen in various studies: perhaps different people need different, even opposing, treatments at the various stages of neurodegenerative conditions.
While personalized medicine is a dream of most in the medical field, microglia are allowing us to slowly turn that dream into viable treatment options. Tell us in the comments section below of any ongoing research or studies you’ve read or are involved in!
