By Medeea Popescu
Aches and pains, slower recovery, worse sleep: many of us are familiar with the physical changes that arise as we get older. As our cells age, no aspect of our physiology is immune—not even the immune system! Infections that we could have beat easily as children or teenagers take longer to clear and recover from.
Our brains are aging too: 5 million individuals in the US currently live with dementia, Alzheimer’s and other neurodegenerative diseases. Emerging data from the new field of brain-immune interaction suggests that the aging immune system actually plays a major role in age-related brain disease.
Katrin Andreasson, a professor of neurology and Wu Tsai Neuroscience Institute affiliate, has spent her career investigating the basis of neurodegenerative diseases and acute brain injuries, such as stroke, in the aging population. Andreasson and her lab have shown that blocking dysfunctional immune responses can reduce brain damage following stroke and reverse age-related neurodegeneration, among other work.
For decades, scientists considered the brain an “immune-privileged” environment, meaning that the few immune cells that made it past the blood-brain barrier didn’t do much. This paradigm has been largely overturned in the last few years, as researchers have discovered that immune cells are a key component of the brain ecosystem. Andreasson has shown that as we age the immune responses that once helped us recover from traumatic brain injuries and fight pathogens actually start doing more harm than good. She and her lab are working on finding novel immune pathways that play critical roles in maladaptive brain inflammation and understanding how these responses cause neurodegeneration.
We spoke with Andreasson about cells gone haywire, funding struggles, and what you can do to protect your aging brain.
You’ve done groundbreaking work on the role of inflammation and the immune system in neurodegenerative diseases, acute brain injuries, and aging—How did you originally become interested in these questions?
It actually started after my postdoc—there were these very interesting large-cohort epidemiological studies of cognitively intact, aging people. The researchers were looking at the association between the use of NSAIDs, such as ibuprofen or naproxen, and neurodegenerative disease. These inhibitors block a well-understood inflammatory pathway called the COX-2 pathway. The studies found that long-term use of NSAIDs correlated with a significantly reduced risk of developing Alzheimer’s.
We wanted to figure out whether the COX-2 pathway had anything to do with development of early-stage Alzheimer's. We made a mouse strain that had increased COX-2 pathway activity, and sure enough, those mice got terrible inflammation, memory loss, and neuronal loss. And so that's how everything started!
Why has it taken so long for the scientific community to begin investigating the brain’s immune system?
It’s a great question. It was really hard initially for us to get funding for this idea, and probably it was because the Alzheimer’s field was very focused on amyloid as a cause of the disease, and it was too far a stretch to consider other mechanisms. Following up on the epidemiology nearly broke me! I'm an MD, and I almost left for clinical practice twice, because it was just so hard to get enough interest in this new concept and find funding.
But what was convincing enough to change the prevailing viewpoint was the publication of human genetic studies for Alzheimer's disease starting in 2013. Over half of the genetic variants associated with the disease are inflammation-related and many of these are expressed in innate immune cells. If that's not convincing that immune cells have a causal role in this disease, then I don't know what is.
Given the research over the past few years, how would you describe the role of immune cells in the healthy brain?
There's a very rich literature on microglia, the primary innate immune cells in the brain. They're very important in sculpting neural circuits. Microglia prune synapses that aren't working or that are not supposed to be there, so they’re critical during brain development in establishing our circuitry. And then once those circuits are established, there's a lot of learning and memory that occurs which creates new neuronal connections. Microglia also secrete growth factors that maintain synapses. And finally, microglia are carrying out basic immune functions like patrolling the brain microenvironment and making sure there are no infected cells or misfolded proteins that can injure synapses and cause neurodegeneration. They really are good guys—they have a very important function in keeping the brain pristine and working well.
In your work, you’ve described how inflammatory signals in aged mammals can cause immune cells to go haywire and worsen brain pathologies such as stroke or Alzheimer’s. Can you summarize what we know about why the immune system can make brain injuries worse?
When you have a traumatic brain injury where you have a massive shearing of axons and cellular debris and dying cells, the insult to the brain is huge. Just like an injury to any other organ, such as a heart attack, a huge immune response is elicited. The innate immune cells are the first responders. In a younger person, these immune responses are generally appropriate and restore an environment where repair and regeneration can occur. But in an older person, the cells are already somewhat compromised because of the effects of age on their metabolism and function. They may try to respond appropriately, but they won't be able to resolve the inflammation. Aged innate immune cells can't turn off the inflammation the way they're supposed to, or they can't clear and remove all the highly inflammatory cell debris. And that leads to excessive sustained inflammation and in the brain, eventual neurodegeneration.
In chronic neurodegenerative diseases like Alzheimer’s, the same dysfunctional immune responses are occurring, except that they’re taking place over a longer time frame while the acute injury is a much more rapid example of the same thing. It’s a similar innate immune response that's involved in both disease states.
It seems like the immune system can do as much harm as good in the brain! Do you have any speculation about why these maladaptive immune responses develop as we age?
Well, it's a great question. Why would you have these damaging pathways? We know the innate immune response is supposed to protect you from pathogens. In general, these immune cells do function to protect us and clear bacterial or viral infections in the brain, and so they are necessary.
But the question is why do they become more of a hindrance than a help as you get older? One explanation could be that the cells in an aging individual just don’t do a good job of regulating these inflammatory pathways. An example is that the COX-2 inflammatory pathway increases in strength significantly with aging, with negative consequences on immune cell metabolism and function. Aging is probably not what nature intended—we're supposed to reproduce and then succumb to infections.
You’ve published on experimental interventions to block excessive immune responses in the brain. Do you see these therapies reaching the clinical trial stage in the near future? What kind of impact could these agents have on how we treat brain injuries and neurodegenerative diseases?
Developing an effective therapeutic is very difficult, takes a very long time and is extremely costly. However, if you could reprogram aged human innate immune cells to a healthier metabolic state, which is what we have shown in our recent study, then these “reprogrammed” immune cells would promote a healthier immune response systemically, and this would benefit the brain and other organs that suffer from the aging process. I probably have a little bit of a bias since I'm a clinician, but I would really like to see something to help patients—effective, disease-modifying treatments are and few and far between in neurology.
Since there’s not a magic bullet yet, is there anything that people could do as they're aging to slow the negative effects of the aging immune system on the brain?
Well, the big one is exercise. We don't have any disease modifying therapies in the clinic yet, but what we do have is strong published research showing that exercise and a Mediterranean diet reduce inflammation and promote healthy aging.
Wu Tsai Neuro just launched the Knight Initiative for Brain Resilience, based at Wu Tsai Neuro, that will focus on taking a big picture look at the biology behind both brain degeneration and healthy aging. What are your thoughts on the initiative’s goals & how do you hope it moves the field forward?
I think it's just terrific and very timely as well. I was one of several colleagues who provided input early on as Bill Newsome [the director of the Wu Tsai Neurosciences Institute] was developing the vision for this new initiative. It is a tremendous opportunity for the Stanford neuroscience community—this initiative will accelerate our understanding of what mechanisms drive neurodegeneration and how we can prevent and reverse it.