Cleaning while we sleep: a novel approach in Alzheimer’s research

We highlight the work of neuroscientist Jeffrey Iliff (Oregon Health & Science University) for this year’s World Alzheimer’s Day on 21 September.

Every 67 seconds, an American develops Alzheimer’s disease. It affects 5.3 million people in the US and if no medical breakthroughs to prevent or cure the disease are found, this number will triple by 2050. But researchers are on the case...

In 2013, Jeffrey Iliff helped discover how our brains flush out toxic waste as we sleep. This is waste that builds up in our brains during the day – including the Alzheimer's-linked protein, amyloid beta. His findings, which he’s advancing by the day, could potentially lead to the treatment, and maybe even prevention, of Alzheimer’s. We catch up with him to find out about how his work has developed over the past few years, the unforeseen twists and turns that led him down this important avenue, and what he looks for in the next generation of Alzheimer’s researchers.

ResearchGate: Why are our sleeping brains pertinent to our brain cleansing system?

Jeffrey Iliff: It seems that sleep has evolved to maximize a bunch of maintenance-type functions in our brain, and this cleaning process one is just one of them. It’s arguably not even the most important one. But for whatever reason, our brain function is optimized when these housekeeping functions happen during sleep, allowing us to maximize our performance while we’re awake. But why that is we don’t really know yet.

RG: You helped discover an important potential link between sleep and the development of Alzheimer’s disease. What were your key findings?

JI: There are two main findings in our research that everything else rests on. The first is in a paper we published in 2012 about cerebrospinal fluid circulation. This is the fluid that surrounds the brain. We were able to show that a substantial portion of it is actually recirculating back into and through the brain. It does this by essentially using the blood vessels as a scaffold to provide access to the entire brain tissue. The movement of this fluid along vessels and through the spaces between the brain’s cells appears to be involved in the clearance of amyloid beta out of the brain interstitial fluid.

The second main finding relates to a paper we published in 2013. Here, we showed that this cleaning process is primarily a feature of the sleeping brain. Both the movement of cerebrospinal fluid along the outside of blood vessels and back through the brain, and the clearance of amyloid beta, occur much more rapidly in a naturally sleeping and anesthetized brain, compared to the waking brain.



Dynamic imaging of the vasculature in the brain

RG: How has your research developed since this finding? What new information have you bought to light?

JI: To boil it down, our current research focus is essentially to analyze what’s going wrong within this cleaning system at a molecular level, and then to translate that into human subjects.

Firstly, our last few papers have shown that in both the aging and injured mouse brain, this cleaning of the brain slows down. We want to define on a molecular and cellular level what’s going wrong in the aging and injured brain that’s slowing down this process, and whether that makes it vulnerable to amyloid beta deposition or tau aggregation.

But at this point, none of this work has been validated in humans – we don’t really know if this cleaning process happens in the human brain during sleep, much less whether this process contributes to the development of Alzheimer’s in people. So I’m excited that we’ve received funding from the Paul G. Allen Family Foundation to look into this. They are funding our group to extend our work on sleep and the aging brain – essentially from mouse models into humans. The first step in that process is to develop clinical imaging approaches to measure the system’s activity in the sleeping and waking human brain. The study will then move on to analyze that process in the aged human brain, and in the brains of people who appear to have the beginnings of Alzheimer’s disease.

RG: How might your research and recent developments help prevent Alzheimer’s disease?

JI: The encouraging thing is that there’s an increasing push on the therapeutics’ side to identify people who don’t have Alzheimer’s disease yet, but are expected to at some point in the future. That’s one of the motivations behind the development of amyloid PET imaging and cerebrospinal fluid biomarkers, for example. A study that just came out of Washington University in St. Louis reported that CSF biomarkers consistent with Alzheimer’s disease could be detected as early as 45 to 55 years of age. If amyloid deposition begins that early, then it’s possible the failure of this clearance system is happening even earlier. So, if we can develop imaging approaches that aren’t prohibitively invasive, then it may be possible to identify people who may be susceptible to amyloid beta deposition in the decades to come. That would offer a very wide window for lifestyle interventions, or drug therapies if effective drugs can be developed.

That’s the really exciting and promising thing for the future: First, this cleaning system may be a new therapeutic target, and imaging it may allow us to develop a new biomarker that identifies vulnerability at an earlier stage in the disease process than our current biomarkers can.

RG: How long do you think it will take to reach this point?

JI: A number of important things still need to be done. I think we’ll know whether these ideas have legs and traction in the next three to five years. If the function of this system can be validated in human subjects, and if its impairment can be causally linked to amyloid beta deposition, then things move on to identifying drugs that might modulate this pathway. That can go quickly or slowly depending on what the data looks like.

RG: Has your research taken any unexpected turns?

JI: The magnitude of the sleep-wake effect was very surprising. But admittedly, all of this research has been one big, unexpected turn that we’ve been trying to chase and learn from along the way. My background isn’t in Alzheimer’s disease or sleep at all – it’s in vascular physiology. I started my postdoc in a glial cell biology lab and thought I’d be a basic science researcher for the duration of my career. The shift to clinical subjects and clinical samples wasn’t something I anticipated, but it’s probably been the most exciting thing that’s happened in my career.

RG: What event sparked the change in your career?

JI: For my PhD, I studied the regulation of brain blood vessels, which is really a largely vascular subject. At the beginning of my post doc I went to talk to my supervisor, Maiken Nedergaard, and she showed me a paper written in 1984. It was by the American neuroscientist Patricia Grady about the movement of cerebrospinal fluid tracers into the brain along blood vessels, and was a somewhat controversial paper at the time. I was only five years old when the study came out, so when Maiken said, “I want you to redefine water movement in the brain,” I had almost no idea what that meant at all! It was a whole field that at the time I knew nothing about, and she knew very little about. So almost from day one it was like we were wandering out into the middle of nowhere, and then we happened to hit this major road – a road that has been very, very interesting. And we’ve been working on it together, and then separately in our own labs, ever since.

RG: What was your greatest ‘eureka’ moment in the lab?

JI: The biggest eureka moment for me was when I was doing the dynamic imaging of the vasculature in the brain. I now use these videos in every talk that I give because they are so evocative. It’s like this: the blood vessels are always red and the tracer we inject into the cerebrospinal fluid circulation is always green. You see the red blood vessels there, and then the green tracer runs into the screen along the outsides of the vessels – it forms a halo around the blood vessel as it moves through the perivascular space. The first time I saw that it really struck me because I was expecting something very, very different. I thought the green cerebrospinal fluid would flood over the screen, for example. But instead, it was restricted to this very narrow, anatomical pathway; it was so specific in where and how it moved. The fact I could see it happening in front of my eyes in real-time, and follow and chase it around, made it very real for me. And then the videos that come from this imaging are extremely believable and compelling for other people, too - in a way that an image of fixed tissue in a paper isn’t. So that was a big moment – one that drove me forward in my research.



Dynamic imaging of the vasculature in the brain

RG: You have a postdoctoral position open in your lab. Do you have any advice or tips for people thinking of applying, or for those entering your area of research?

JI: When I’m looking for a post doc I’m not looking for a technician. I can get hands – that’s not a problem. What I want is people who have better ideas than I do; I want people in my lab who are more creative than I am, and that can bring something new that’s going to change my science. Having a different background is extremely valuable because you can offer a new take on the science that we’ve been looking at the same way for the last 5 years.

I’m also looking for someone who has a defined idea of what they want to do when this post doc is over. Many applicants don’t have a clear vision of how they’re going to become an independent researcher – which is an end goal I hear a lot. My goal is to help them get there, I’d love to do that. But if they haven’t thought of how their science and my science can interact in a way to get them there, then they’re missing a critical step. In the interview I want to see this drive, energy, creativity, and familiarity with our work. And that’s because when I hire for these post doc positions, I’m looking for a potential partner.

Dynamic imaging of the vasculature in the brain - courtesy of Jeffrey Iliff; feature image courtesy of K. Kendall

This interview was republished on the Oregon Health & Science University news blog.