A Tale of Two Cells: Teasing Apart the Immune Response in Alzheimer’s Disease
It was the best of immune responses; it was the worst of immune responses.
At the nascence of Alzheimer’s disease research, it was a common belief that the suspects of the associated cognitive decline and memory loss were beta-amyloid plaques —a type of brain debris that can clog brain cells, leading to the loss of crucial memories. However, as research in the field progressed, it became more apparent that the immune system played an increasingly important role in Alzheimer’s disease pathology and progression.
Immune cells are responsible for fighting infections and diseases within the body by ingesting and degrading harmful materials. Immune cells can be found in all areas of the body; however, identifying the specific cells involved in brain immunity has proven to be difficult.
Imagine that you are tasked with visually differentiating two identical twins. For the most part, they are exactly the same —same clothing, same hair style, same behaviour. However, the two individuals lead completely different lives and have completely different skill sets. From the outside, it would be next to impossible to tell them apart just by observing them together. Of course, the task of visually differentiating the two twins would be substantially easier if one twin was conveniently tagged with an item of clothing, such as a wristband, while the other was not.
This scenario can be applied to two immune cells found within the progression of Alzheimer’s disease. The first type are microglia – tiny immune cells that take up permanent residence in the brain and work behind the scenes to clean up harmful brain debris such as beta-amyloid plaques. The second type of cell are macrophages, immune cells typically found in the blood but can travel to different organs to fight infection throughout the entire body.
Normally, microglia and macrophages can be differentiated by where they live; however, in the case of Alzheimer’s disease, both cell types are present in the brain together and are visually indistinguishable from each other under a microscope.
Much like the identical twin scenario, if only there was a way to tease apart these two visually identical cells in the brain, scientists would be able to better characterize how each type of cell contributes to the progression of Alzheimer’s disease. Interestingly, a recent article published in 2020 by Dr. Natalie Kozyrev, led by Robarts scientists Dr. Gregory Dekaban and Dr. Jane Rylett at Western University, highlighted a new way to differentiate resident microglia from blood-derived macrophages in a mouse model of Alzheimer’s disease.
What makes Kozyrev’s Alzheimer’s model different from other mouse models in the field is that blood-derived macrophages can be easily spotted. These cells were genetically tagged with an enhanced green fluorescent protein, or eGFP, much like adding a wristband to distinguish one twin from another. Since no other cells in the brain express eGFP, Kozyrev’s team could be confident that green cells in the brain, when imaged with a microscope, were blood-derived macrophages instead of microglia, which were identified using an immune cell (and microglial) marker, IBA-1.
With this effective model in hand, Kozyrev’s team was able to characterize the immune cell population that aggregated around amyloid-beta plaques, indicative of Alzheimer’s disease progression. Firstly, Kozyrev’s team noted differences in Alzheimer’s progression between male and female mice; specifically, female mice showed more beta-amyloid plaques at younger ages compared to male mice at the same age. This is similar to what is seen in humans, in that women are more likely to develop Alzheimer’s than men.
On top of this, Kozyrev also saw differences in the population of immune cells surrounding the beta-amyloid plaques with age. Out of all immune cells surrounding amyloid-beta plaques, blood-derived macrophages outnumbered microglia. With age, the ratio of macrophages to microglia became even larger, meaning more macrophages were affiliated with the beta-amyloid plaques compared to microglia. It was important to note that while the population of macrophages residing around beta-amyloid plaques increased with age, the amount of microglia residing around the plaque did not change over time.
Why does it matter how many microglia or macrophages surround amyloid plaques? Thinking back to our identical twins, despite being visually similar, each twin could differ in terms of their profession. For example, one could be a chef, while the other could be a waiter – although both can be found working in a restaurant, each twin has a very different skillset. Likewise, macrophages and microglia are employed under the immune system. Unlike the chef and the waiter, it is still unknown whether macrophages and microglia can combine their skill sets to help slow Alzheimer’s disease progression, or if their skill sets are incompatible, causing an ineffective immune response that further promotes Alzheimer’s progression.
Experiments performed by Kozyrev’s team can help scientists uncover how these cells differ in their specific functions. By understanding which cell types surround beta-amyloid plaques, and importantly, when these cells begin to emerge, scientists and clinicians may be better able to diagnose Alzheimer’s at an earlier stage, potentially preventing the devastating progression of the disease. Uncovering if and how macrophages and microglia work together in the brain during the progression of Alzheimer’s is crucial information that can be used to develop a treatment to slow or stop the progression of the disease altogether.