Bioenergetics: How Mitochondria Affects Alzheimer’s Disease and Aging

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters.Over the past few decades, a growing field of Alzheimer’s disease research has been bioenergetics. Focusing on the flow of energy throughout cells, bioenergetics is interested in how metabolic processes involving mitochondria transform energy in the body. What happens when these processes change and act abnormally? One theory is neuronal dysfunction, a core feature of Alzheimer’s disease, leading researchers to turn their attention to bioenergetics as a pathway for treating and preventing Alzheimer’s disease. Here talk with us about this field of research and what it's finding is Dr. Russell Swerdlow, a professor of neurology and director of the University of Kansas Alzheimer's Disease Research Center and recent recipient of the Oskar Fischer Prize for Innovative Alzheimer's Disease Research. Dr. Swerdlow's work focuses on brain energy metabolism and its connection to Alzheimer's disease. Dr. Swerdlow, welcome to Dementia Matters.

Dr. Russell Swerdlow: Thank you Nate! It's a pleasure to be here.

Chin: I'd like to start by asking how you got into this field of mitochondria, bioenergetics and Alzheimer's disease?

Swerdlow: Well, in college I was very interested in neuroscience and I was a bit of a biochemistry nerd. I really liked metabolism. I had a grandmother who had Alzheimer's. I think that no doubt had a big impact on my career trajectory. I went to NYU undergrad and matriculated into the medical school, and the summer between my graduating as a senior and starting medical school I needed a summer job. I thought it would be great to get a job doing biomedical research in a lab. I went to the medical school and asked if they had any research positions and looked for a position that was dealing with Alzheimer's disease and biochemistry. I was very fortunate; there were three faculty members at the time, Moni de Leon, Steve Ferris, and Barry Reisberg who were doing FDG-PET research on Alzheimer's patients. They appreciated the problem with glucose utilization on FDG-PET and they had convinced two other investigators at the university – Mike Friedman and Dave Markus – who had a biochemistry wet lab to study the biochemical correlates of what they were seeing on the FDG-PET scans. It sounded real exciting to me and that's the – that's the lab that I entered into actually in 1987. At that point I started studying glucose utilization in Alzheimer's brains. Then I learned about something – actually during my first year biochemistry class as a medical student – listening to the lecture on fatty acid chemistry and learned about something called a ketogenic diet and how the brain can run off of ketone bodies. I began to wonder how might the Alzheimer's brain handle ketone bodies, so I went back to the lab and asked if I can study that, got the okay, and spent the next couple of years doing that. I noticed that there seemed to be an overlap in where metabolism was breaking down with both ketone body and glucose utilization. Where that overlap occurs is in mitochondria. So I began thinking, could there be a problem with mitochondria in Alzheimer's disease? After I graduated medical school, I went to do my neurology training at the University of Virginia. I was very fortunate to cross paths with a faculty member named Davis Parker, who had recently described the cytochrome oxidase defect in people with Alzheimer's disease. He had this really neat idea that mitochondrial DNA, in addition to perhaps accounting for low cytochrome oxidase activity in Alzheimer's patients, might also help explain the sporadic nature of diseases with genetic components. My project that I took on at the time was trying to determine the basis of the cytochrome oxidase defect in Alzheimer's and that worked out. Oh I don't know, twenty five years later here I am.

Chin: That's incredible! So you weren’t initially someone who said, ‘Oh, mitochondria!’ It sort of was a process that led to your work in it.

Swerdlow: Yeah. Certainly in the 1980s, the field was a lot more of an open book. There really wasn't an amyloid cascade hypothesis and the big question was are plaques and tangles a cause of Alzheimer's disease or are they a consequence of it. I don't know, for whatever reason it always seemed to make more sense that perhaps they were a consequence.

Chin: Before we go forward with your research, I'd like to establish some background for our listeners. In particular, what exactly are mitochondria and how are they related to aging in the human body?

Swerdlow: Well, we all learn in high school that mitochondria are the powerhouse of the cell. They provide the energy that we need and energy is important. I mean, we need it to combat entropy. It's the spark of life. We really can't – well, we absolutely can't survive without it. The way that mitochondria make energy is a very intricate process, and the way that they fit in within the greater cell milieu is a very intricate process. When the cell environment is not right, things are not right with the mitochondria. And when things are not right with the mitochondria, then things go bad for the cell. One of the things that I always thought made mitochondria an attractive candidate for Alzheimer's etiology is the fact that they are linked to aging. They are recognized as one of the hallmarks of aging and, in fact, mitochondrial dysfunction can drive aging phenotypes.

Chin: So dysfunction or problems of mitochondria lead to some of the things that we see as people get older?

Swerdlow: Yeah. Our mitochondria certainly change as we get older. Certainly some of those changes that we see in mitochondria are going to be the impact of aging on mitochondria, but also some of what we appreciate with aging is probably being conferred and induced by mitochondria themselves. One thing that we really need to do is try to understand what the aging clock is. That's a very important principle in aging research. There's pretty good data that mitochondria at least in part contribute to the aging clock, but there is no controversy that our mitochondria changes as we age. To the extent that mitochondria contribute to that, that's what many people refer to as the mitochondrial theory of ageing.

Chin: With that background in mind, what leads you to believe that mitochondria are different in Alzheimer's disease and its dysfunction a key cause or process within Alzheimer's disease?

Swerdlow: Yeah, there's really no doubt that mitochondria are altered in Alzheimer's disease. We've known that for decades. Even back in the 1970s people doing work with electron microscopy noted that mitochondria just looked different in the brains of Alzheimer's patients. Now there could be good reasons for that. Maybe the brain is not working right? Maybe the mitochondria are not going to function right and mitochondrial biology is going to be altered? But the mitochondria just look different. Then really starting in the 1980s, investigators began to report that certain enzymes that are localized to mitochondria are not working the same way as they are in people without Alzheimer's disease. There were people like Gary Gibson and John Blass who reported that certain Kreb cycle enzymes and pyruvate dehydrogenase complex that activities with those enzymes were reduced. Davis Parker, as I mentioned before, reported reduction in the cytochrome oxidase activity and there were researchers who actually performed respirometry experiments from biopsy samples taken from Alzheimer's patients in the 80s which showed problems with mitochondrial function and integrity. One of the things that I think is really critical is that mitochondrial changes in people with Alzheimer's disease is not limited to the brain. We recognize that with people with Alzheimer's disease, we can pick out changes to mitochondrial function in platelet mitochondria, fibroblast mitochondria, muscle mitochondria. In that context, it's kind of hard to explain those changes on the basis, let's say, of beta amyloid or or to say that they're simply a consequence of neurodegeneration. Now that’s not to say that some of what we see in the brains of Alzheimer's patients isn't due to beta amyloid or neurodegeneration, but it can't account for all of it. These were some of the principles that allowed me and others – collaborators and mentors, mentees – to begin to really conceptualize the mitochondrial cascade hypothesis or or what I would refer to specifically as a primary mitochondrial cascade hypothesis.

Chin: And let's get into that, because that was one of my questions for you. In receiving your award that I mentioned earlier, one of the things they talk about is that you have been at the forefront of this mitochondrial cascade hypothesis. What exactly is that?

Swerdlow: The primary mitochondrial cascade hypothesis is my attempt to synthesize a lot of data, a lot of information, a lot of what we know about Alzheimer's disease and mitochondria and energy metabolism in Alzheimer's disease to perhaps give some perspective as to what might drive Alzheimer's. As a clinician who takes care of Alzheimer's patients, I'm struck by the impact of aging. Any viable Alzheimer's disease hypothesis, I think, has to take into account aging and why aging is the greatest risk factor. I think mitochondria covers that well. The assumptions of the hypothesis are that we inherit a baseline state of mitochondrial function. Each person inherits their own baseline state of mitochondrial function that comes from or that is determined by genes that we inherit, nuclear genes that we inherit from our dads and from our moms, and from mitochondrial DNA that we inherit exclusively from our moms. The idea is that as we age, our mitochondria are going to change. How rapidly they change is determined by our genetic makeup and also by our environment, how well we take care of our mitochondria. Eventually, we reach a point where our mitochondria change enough that they trigger the proteostasis changes that we appreciate in Alzheimer's disease, the plaques and the tangles, and also a number of systems changes, like inflammation and insulin resistance changes in lipid biology, that we see in Alzheimer's patients. Those systems changes and proteostasis changes may then feed forward and further impact the mitochondria, or not, but as an individual continues to age and their mitochondria continue to decline the thought is that we reach a point that we can no longer compensate and we depart from a state of compensated aging to a state of decompensated aging and experience the cognitive decline in dementia and the degeneration of Alzheimer's disease.

Chin: Just to summarize some of the key things that I took away from that, Dr. Swerdlow. One is that mitochondria are in all of our cells, not just brain cells. Seeing changes in other cells outside of the brain does really lead one to believe that Alzheimer's cannot simply be amyloid and amyloid plaque and tau tangles, but there's clearly something else going on to. Two, mitochondrial DNA comes from our mother. This is, I mean in general – for the general public listening you think of DNA coming from both mom and dad, but in this regard mitochondria specifically coming from our mothers. Then knowing that mitochondria then change or respond to our environment and that some of those changes lead to changes in its own function, which can then change as you said compensation or lead to decompensation, so it's a whole system. It's a whole network of different things but mitochondria being a really critical piece of that.

Swerdlow: Yeah, absolutely I think you nailed one of the core issues, which is at the biochemical level Alzheimer's disease is really a systemic process. What's driving what? Are the changes in the brain driving things outside the body or what's going on throughout the entire body, are they also playing out in the brain as well, in a unique way?

Chin: Now you've also mentioned amyloid and tau. We talk about that a lot on this podcast. What, if any, is the relationship between mitochondria and these proteins of Alzheimer's amyloid and tau?

Swerdlow: Yeah, so that's a great question. We don't know all the answers, but the central assumption is that changes in mitochondria lead to changes in cell biology that then will set up the situation for plaques and tangles to develop. There is not a gene for beta amyloid. There's an amyloid precursor protein gene; there's an APP gene. APP is – its expression and how it's handled in cells is affected by what goes on in the cell. Something in APP biology changes as we get older. I appreciate that – yeah, you can get a stochastic, let's say, misfolding of beta amyloid and that seeds things and then maybe perpetuates, but even if that is the case changes to APP biology and how the body handles Aβ, that's not happening in a vacuum. The body seems in general to, and the brain seems in general, to have greater problems in proteostasis as it ages. I do think that changes in mitochondrial function set the stage for the changes in APP biology and tau biology and TDP43 biology that we associate with Alzheimer's disease. Whether those changes in proteostasis further damage the mitochondria, I'm fine with that. The hypothesis is fine with that. They may or they may not. It's just that something must set the stage, and I would guess it's probably the mitochondria.

Chin: And so in talking about biomarkers because that's a huge field within Alzheimer's disease and in particular amyloid and tau biomarkers, but there's also this conversation and discussion of the need for other biomarkers in understanding cognition, cognitive health, cognitive decline. With this importance of mitochondria, are there any biomarkers for mitochondria and, if not, how can one actually measure mitochondria and their function?

Swerdlow: Yeah, so biomarkers for Alzheimer's disease, especially ones that will tell us about the state of someone's mitochondria, we're working on that. I know there are groups that are working on that. There are challenges. One is spatial. We can get a sense of maybe the state of someone's mitochondria, or what I would refer to as their bioenergetic infrastructure in their brain, using imaging. Some of the limitations of using imaging is that it gives us an indirect view or may not be very sensitive. FDG PET, for example, gives some insight into brain metabolism but only rather indirect inferences about what's going on with mitochondria. There are other PET ligands that people are working on that I think are going to be able to give us more insight. For example, being able to tell us what the mitochondrial mass is in someone's brain. The field is making progress there. Alternatively, you can get more sensitive if you can actually get tissue. We don't get brain tissue in our living patients. We can get blood, maybe fibroblasts or muscle. That allows us to really drill down into what the mitochondria are looking like, what they're capable of or not capable of, but it's not the brain. I mean, how are we going to reconcile that? You know, the field will find a way. The technologies will get better. You know, maybe spinal fluid or exosomes will help out. But the other thing too, which I would throw out just to be provocative, which is that some of us here in Kansas might actually view cerebrospinal fluid beta amyloid as being a mitochondrial biomarker.

Chin: Wow, I don't even know how to respond to that. That’s very interesting! Your field or your Kansas center in particular, you guys are looking at that as well as how are other ways for us to identify and sort of track mitochondrial function?

Swerdlow: Yeah, that certainly is a focus of our biomarker core. We're into technology development but also just asking questions and following the data. Some of our data indicates that APP targeting within a neuronal cell is impacted by the state of its mitochondrial function. So when mitochondria are active, a lot of APP makes it to the synaptic membrane and Aβ is generated and secreted into the spinal fluid. When mitochondria are less active, they siphon off APP to the mitochondria, unless it makes it to the plasma membrane and secreted Aβ goes down. We think that this may help explain why Aβ levels are low in spinal fluid of Alzheimer's patients, and in so, in that respect, Aβ may actually be a biomarker of mitochondrial function.

Chin: Wow! And then I guess one of the things I'm wondering, now that you've established this background on mitochondria, is there anything that we can do now to improve the health of our mitochondria or increase the number of mitochondria that we currently have?

Swerdlow: Yeah I think so. We're very focused on that in our therapy development and prevention efforts. We take cues from lifestyle interventions such as exercise and diet. For example with exercise, if you're training to run a marathon what your training does is it increases your mitochondrial mass in your muscle and that allows you to run farther. With certain diets, you can change your mitochondrial infrastructure. For example, in particular in the liver. It looks like there is some leakage of how these interventions impact the brain as well and we're trying to understand why and how so that we could develop drugs that will do the same things only more powerfully. I think that we will develop drugs that can alter the state of someone's brain mitochondria and our brain bioenergetic infrastructures. Actually, we recently published a paper in which we showed that – a proof of principle study that we can impact brain energy metabolism through interventions.

Chin: In past presentations that you've given, you've mentioned the ketogenic diet. You mentioned it earlier today in our discussion. You've talked about its effect on the brain. Is there a relationship between the ketogenic diet and some of these mitochondrial processes, these critical processes that you've talked about?

Swerdlow: Yeah, well, my interest in the ketogenic diet is essentially a proof of principle interest. It's a way of changing the cell's energy metabolism infrastructure. If you change the fuel that neurons are using, the energy metabolism infrastructure is going to change. We've done studies to look at how it changes. Actually, we published a study about a year ago in which we had placed mice on a ketogenic diet for three months and then harvested their neurons and performed RNA-Seq (RNA sequencing) with KEGG analysis. In other words, we looked at the transcriptomic changes that were occurring in the neurons and then we used software – the KEGG software – to look and see what diseases would be expected to be impacted by a ketogenic diet. The disease that rose to the top of the list, interestingly, was Alzheimer's disease. The reason is that in the brains of Alzheimer's patients the expression of genes that support insulin signaling and oxidative phosphorylation are going down, but with a ketogenic diet the expression of genes that support those pathways becomes upregulated. We think we can impact brain energy metabolism and through that the rest of the brain. We've done a pilot study of a ketogenic diet in Alzheimer's patients, which was promising enough to move us to the next step of doing a larger randomized trial that we hope will give us more reliable insight into how the diet may or may not benefit people with Alzheimer's disease. Again, the goal is not – even if a ketogenic diet does appear to help people with Alzheimer's, the goal is not to get people on a ketogenic diet. The goal is to take away what we can learn from that and then use that r to further drug development.

Chin: Well, that's incredibly exciting and I'm sure we would love to have you on after we have results from those studies. It also leads to my last question which is, what's next in this line of research and what are you most excited about?

Swerdlow: Well, the thing that I'm most excited about, after thinking about these mitochondrial cascades for decades, is I feel like I'm getting a more specific sense of what's going on. For several decades, I've been working from the perspective that mitochondrial DNA is a relevant event contributing to Alzheimer's risk, or at least Alzheimer's. I'm beginning to get a sense that mitochondrial DNA copy number is probably important. Also if you're going to go out and try to sell a hypothesis like this, obviously one thing you need to be able to do is to tie it into the classic histologic hallmarks of Alzheimer's disease – the plaques and the tangles and ApoE biology. I think that we're making pretty good progress in that respect as well. It's a lot of basic biochemistry, basic molecular biology, fundamental biology. I'll put it this way – as I continue to study these questions, my thinking on everything continues to mature. I guess one of the things that I'm really excited about is that the more I learn, first of all the more humbled I am and the more I realize I don't know and that I need to know. At the same time, the basic premise seems to me to make more sense rather than less sense, so that's pretty exciting. If we can continue to make progress on these basic issues - why exactly are mitochondria going down? Why are they going down with aging? How is aging tied into it and how does this all tie into things like plaques and tangles? And then all the other things that we see in Alzheimer's, not just limited to the brain but extending it into our other physiologic systems as well. Ultimately my main hope is that through this understanding, we will get some insights into therapeutics and use those insights to guide therapeutic development and that ultimately this will lead to better therapies for Alzheimer's disease. The best test of all of a hypothesis, I guess, is how well it ultimately fixes the problem it was designed to explain.

Chin: Well with that, thank you, Dr. Swerdlow, for being on Dementia Matters. We sure hope to have you and members from the Kansas ADRC back here.

Swerdlow: Thank you Nate! It was a real pleasure.

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin--Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.