How the brain’s immune cells both help and harm in cases of Alzheimer’s
A trio of new studies are investigating the role our brain’s immune cells play in the progression of Alzheimer’s disease. Researchers are revealing how these immune cells can contribute to neurodegeneration, and how they may be harnessed to prevent neuron damage.
Our brains carry their own unique immune cells called microglia. These cells constantly patrol our brain, cleaning up damaged neurons, clearing out toxic proteins and fighting off damaging pathogens. As microglia are fundamental to both activating and resolving inflammation their role in the progression of many neurodegenerative diseases has been the focus of much recent research.
The main pathological hallmarks of Alzheimer’s disease are accumulations of two toxic proteins, amyloid-beta and tau. In generally healthy brains, microglia maintain a balance by clearing out those proteins before they aggregate into damaging deposits.
One new study, led by a team of German researchers from the University of Bonn, is trying to determine what happens to trigger the shift from healthy neuroimmune activity to the beginning stages of degeneration associated with Alzheimer’s disease. The research suggests microglia can occasionally die in the process of cleaning out amyloid proteins, and when that happens they release what the study calls ASC flecks.
"Sometimes the microglia cells perish during this process," explains Michael Heneka, an author on the study published in Cell Reports. "Then they release activated inflammasomes into their environment, the ASC specks."
Outside of the brain, inflammasomes such as these ASC specks are generally a good thing. They allow immune cells to react more swiftly to similar infections but in this neurological context they actually result in more cellular damage. The study found these ASC specks cause a damaging feedback loop, binding to amyloid proteins and preventing their degradation while also stimulating more microglial activity and subsequently releasing more and more ASC specks.
"As a result, a fundamentally useful immune mechanism becomes an essential factor in the development of Alzheimer's disease," suggests Heneka.
The novel hypothesis presented in the study is that amyloid proteins only start aggregating into toxic Alzheimer’s causing plaques when this immune-generated feedback loop is triggered. Without the presence of these ASC specks, the researchers hypothesize amyloid proteins don’t trigger neuroinflammation, and don’t cause Alzheimer’s disease. Heneka suggests if this process can be disrupted early on then Alzheimer’s disease may be preventable.
"This might make it possible to treat Alzheimer's disease preventively in the future, so that there is no impairment of mental performance in the first place,” Heneka says.
Another new study, led by researchers from the VIB-KU Leuven Center for Brain & Disease Research in Belgium, is investigating similar mechanisms but from a different perspective. This work is asking what potential genetic triggers could be leading to the damaging relationship between microglia and amyloid proteins.
"Almost every person develops some degree of Alzheimer pathology in the brain, i.e. amyloid-beta plaques and tau tangles,” says Mark Fiers, co-lead author of this new study published in the journal EMBO Molecular Medicine. “However, some people remain cognitively healthy despite a high pathology load, while others develop Alzheimer symptoms quite rapidly."
The study looked at several mouse models of Alzheimer’s and identified 11 new risk genes that are upregulated in microglia when encountering amyloid proteins. What this suggests is that certain genetic triggers may be directly influencing how microglia respond to the presence of amyloid proteins. And it could be this mechanism that explains why some people can present with unexpectedly high levels of amyloid in their brains while not exhibiting any clinical symptoms of Alzheimer’s.
"While amyloid-beta might be the trigger of the disease, it is the genetic make-up of the microglia, and possibly other cell types, which determines whether a pathological response is induced," Fiers explains. "Identifying which genetic variants are crucial to such network disturbances and how they lead to altered gene expression will be the next big challenge."
Although these two studies have looked at what may be causing harmful microglia activity, another recent study is suggesting we may be able to push these neuroimmune cells into helping rather than harming.
A few years ago scientists homed in on a cell surface receptor called TREM2. It was suggested that TREM2 is vital to effective microglia function. Animals engineered to not produce the TREM2 protein were much more susceptible to developing numerous neurodegenerative diseases including MS and Alzheimer’s.
Now a new study is demonstrating the effects of a new antibody designed to enhance positive microglia activity by activating TREM2 pathways. The new antibody has been dubbed 4D9, and early animal tests have delivered positive results. A mouse model of Alzheimer’s indicates the antibody essentially wakes up dormant microglia by enhancing TREM2 expression, and subsequently reduces amyloid deposits.
It is incredibly early days for the antibody research, and Christian Haas, a German scientist working on the project, is very clear more work is needed before this experimental therapy even moves close to human trials.
"We have shown that immune cells can be stimulated to break down amyloid deposits more effectively,” Haas says. “This demonstrates that our approach can work in principle. However, there is still a long way to go before it can be tested in humans and additional data is necessary to validate this approach."
This trio of new studies all affirm the key role played by the immune system in the progression of Alzheimer’s disease. We know inflammation is fundamentally intertwined with the neurodegeneration associated with dementia. Exploring exactly how microglia influence the course of Alzheimer’s may direct scientists to future preventative treatments.