Copper Might Promote Alzheimer’s – Extended Version

 

I’m Shelley Schlender.  This is an extended interview from the report we broadcast on August 20th, 2013, about a new study from the University of Rochester that indicates that too much of an essential nutrient, copper, might promote Alzheimer’s disease.

As background Rashid Deane gave mice drinking water laced with 50 times their normal copper intake. While that sounds high, he says it was only 10% of the daily dose that the EPA considers to be within safe limits for the mice. Rashid says this amount of copper, that’s within EPA limits, led to a reduced effectiveness of the blood-brain barrier, resulting in excess copper in the blood that feeds the mice brains. This activated mop-up proteins, such as beta amyloid and prions. Some research indicates that these proteins, when working properly clear out inflammation. But the excess copper stuck to the clean-up proteins. Altered proteins then clogged receptor channels that normally allow the beta amyloid, prion proteins, and copper all to pass back down, through the blood-brain barrier, and passed to elimination channels, such as the liver. Deane suggests that all this blockage may contribute to the risk of Alzheimer’s.

Deane plans more research to determine whether people with Alzheimer’s have higher blood copper levels. He’s also exploring other substances that prevent the brain from cleansing itself of accumulating “trash.” For instance, high blood sugar levels can clog the receptors that allow toxins to leave the brain. As for copper, everyone needs and gets trace amounts from food, copper plumbing, and supplements. Dean personally points out that he has copper pipes in his home and no plans to replace them.  But given his findings, Deane suggests that for people who get enough copper in their diet, they consider reducing copper supplements for instance. 

To help clarify a couple of technical topics that we’ll mention, in his study, Deane describes how a chemical called N-acetylcysteine helps reduce detrimental effects to to buildup of copper in the brains of the mice they studied. Interestingly, doing a wikipedia search about this supplement, it became clear it’s a substance that is often used to clear out damage from an overdose of a non-steroidal anti-inflammatory drug, such as Tylenol. That led to some interesting questions along the lines of Tylenol.

Also, at the end of this interview, I asked Deane about the nature of Alzheimer’s in other animals, such as salmon. That’s because salmon is a fish that naturally develops beta-amyloid plaques in its brain as part of its normal aging process, and this is a process studied by University of Colorado researchers. The salmon experience leads some researchers to wonder whether beta amyloids plaques might somehow be protective, even in humans. We’ll link to an interview about the salmon on HowOnEarthRadio.org.

INTERVIEW TRANSCRIPT:

Shelley Schlender: Your paper is intriguing. I bet you’ve gotten a lot of calls today about it.

Rashid Deane: Yes, yes, I’ve been on the phone all day today. [laughs]

Shelley Schlender: I was glad to get your actual study, because after reading it, I couldn’t decide whether I want to get my copper pipes checked to make sure that I don’t get excess copper or that I should tell all my friends to be careful about using Tylenol.

Rashid Deane: I think to be careful about how much copper you take in is the best advice, because copper is an essential metal ion and we do need copper to keep our body functional. There are many sources, copper piping, there is some leaching out of copper there, but whether that could be a major contributor, depending on our water supply, which has copper as well, and the food we eat has copper. We didn’t really address copper in food, because we kept that constant. We didn’t really study copper deficiency, and we made sure they (the mice) have enough copper in them, so their food was OK. But we did alter the water supply. The logic there was because in food, to get the copper out of it so it get in the body, it has to be broken down. So the food we take in, the nuts we eat, to absorb any of the copper, it has to be broken down. Copper has to be released in order to get into the body. In the water supply, the copper is already there, and again it’s delivered more rapidly.

So it’s that sort of logic that we are actually studying. Of course, copper in water is a source of copper as well.

Shelley Schlender: In your study, you were using huge amounts of copper, 52 times the amount that the mice normally drink, highly toxic levels of copper.

Rashid Deane: That you’ve got wrong. We’re not using high levels of copper. We’re using 10% of the maximum allowed in our drinking water (by the EPA), it’s 10%. But you’re quite right in saying that the normal water supply for the mice did actually have a lower level of copper than that. And it’s because copper in water varies from area to area up and down the country and in different countries as well. Some areas have very low levels. Also, the mice we have here have special treatments. Their normal water, has been through an autoclave, it’s been heated up to kill all the bacteria and so on in it, and also it’s been filtered before they get it.

Shelley Schlender: For your study, you gave the mice more copper than the mice normally get, but it’s only 10% of what the EPA considers a safe level of copper consumption for humans?

Rashid Deane: Correct. That’s the point. Yes. (Rashind adds that dosing lab mice via the drinking water was used not because he thinks copper in water is a problems, but instead, for experiments, it’s a normal and predictable way to dose an animal. )

Shelley Schlender: It was only 10% of EPA limits for copper?  That’s very sobering. But it still doesn’t finish solving a puzzle, because Alzheimer’s disease is on the rise, as are prion-related, brain wasting diseases. I’m not aware of anyone saying that the amount of copper being ingested by the American public has been going up as well.

Rashid Deane: Well, we actually don’t know that, because we are promoting good health, saying, “Have your nuts, have your vegetables, eat more fish.” And all of these have high levels of copper. As well, the public seems to be very conscious that they must take supplements in addition. I’m sure there are people who, in addition to all of what they eat, containing copper, take supplements as well. And supplements often have two milligrams of copper in a daily dose, which, when added to copper that may be coming from other sources, such as high copper foods, can add up to a lot. So you could potentially have individuals who are eating well as well as taking all of the supplements that are being recommended, and they’re doing it all religiously, and maybe, just maybe, they’re having too much copper.

Shelley Schlender: Perhaps they are. Maybe some people are eating too much copper. I’m not aware of any studies that compare the amount of copper consumption that somebody takes in and their risk of Alzheimer’s disease, but perhaps your study will trigger that kind of investigation.

Rashid Deane:  The study you describe, it would be excellent. The late Dr. Larry Sparks did a survey of water supply up and down the country, and he did find a loose relationship between the level of copper in the water supply and the incidence of Alzheimer’s disease in those areas. So there is some loose relationship out there between copper levels and water supply and Alzheimer’s disease. But that’s fairly loose.  (Deane credits Sparks’s work with stimulating Deane’s curiosity about copper and Alzheimer’s disease.)

Shelley Schlender: So you’d like to see a more clear study of the epidemiology of copper intake versus Alzheimer’s and prion-related diseases?

Rashid Deane: Prion disease is a little bit more complicated. I definitely would like to see a more detailed study in those areas, and you’re quite right, it’s the total copper intake we should look at, what’s in the blood levels and what’s in the food supply.

Shelley Schlender: I think that makes sense to me, too, but I was also fascinated in your study by how you indicated that in the mice, you could reduce the effects of the high copper levels by giving them an antioxident supplement, N-acetylcysteine, that is widely known to reduce the effects of overdose from another chemical – and that other chemical basically is Tylenol.

Rashid Deane: Great! Yeah, I think you made a good observation there, actually, because that’s what we did that experiment for. We’re trying to see if we can find some way of actually preventing or delaying this process (of Alzheimer’s Disease) by giving them some sort of a treatment which is an antioxidant of some sort.

Shelley Schlender: I couldn’t help but wonder, though, whether the increase in use of Tylenol might be associated with Alzheimer’s, by somehow inhibiting the body’s ability to clear out copper in a more efficient way.  After all, for some reason excess copper, from what you’ve mentioned, is harder for the body to clear out out of the brain.   But it’s easier to clear out that excess with the supplement, N-acetylcysteine.  The substance that clears out a Tylenol overdose seems to help with clearing out copper as well.

Rashid Deane: But the compound we use is not related to Tylenol. The compound we use, it’s like an antioxidant. It’s not Tylenol-based.

Shelley Schlender: Correct, it’s not Tylenol-based, but the substance that you used to clear out the blockage to copper, so that the excess copper will wash out of the brain, shows up in general searches about it, as a substance that’s used primarily for clearing out overdoses of Tylenol.

Rashid Deane: Tylenol is cleared out through the liver and everything else, and so is copper as well, and it gets into the bile and it gets out of the gut that way.  But how N-acetylcysteine works with copper compared to with Tylenol is a little bit different.

Shelley Schlender: So those may not be related? It may be that this substance helps both poisonings, but in different ways and for different reasons?

Rashid Deane: In different ways, different reasons, that’s for sure. In the case of the Alzheimer’s disease, the amyloid is actually trafficked across the blood vessel by a special ferry receptor called LRP1.

Shelley Schlender: I found myself calling that LRP1 the “lower-the-inflammation” receptor. I know that’s not its official name, but that’s what it’s doing. Let’s step back for just a second and let’s talk through what happens when all the system is working right.  When things are working right, the blood-brain barrier keeps out most free radicals, including perhaps excessive copper, is that correct?

Rashid Deane: Yeah, the blood-brain barrier is there to restrict the entry of toxic molecules into the brain, and that’s a key point of this paper, actually. This idea is different than those of anybody else. We argue that in normal animals, the blood-brain barrier is intact, and therefore it will restrict the entry of excess copper. If these toxin molecules are not restricted, where do they go and how do they cause the effect? What we are showing here is that the excess copper actually accumulated in the blood vessels, but not in the rest of the brain.

Shelley Schlender: Yes, and that was fascinating, too, that what you see is, if the levels of these toxins increase only in the blood itself . . . let’s talk again about how it works when it’s working right.  First, if excess copper gets into the brain’s blood system, beta amyloids and prion proteins go to the scene to help mop up the inflammatory battle. They’re there to help mop things up, and in a body that’s working right, after everything gets mopped up, then the body pours all that stuff – the used beta amyloids, the prion proteins, and the excess copper, back down through the blood-brain barrier for detoxification and sending out of the body. So that’s when things are working right. Does that sound—that’s a really quick description—

Rashid Deane: Yeah, (It is a quick description!)

Shelley Schlender: But it sounds to me like in your description of what happens when things are going wrong, first of all, too much copper passes the blood-brain barrier in the bloodstream, and then the copper in the brain’s blood binds to a prion protein and messes up its shape. The copper ion switches the prion so it’s shaped wrong.

Rashid Deane: Yeah. (Though Deane points out this is an oversimplification – more details are in his study)

Shelley Schlender: And so the prion ends up clogging up the receptors that let the toxins out of the brain.  That’s an ironic dilemma, since the prion was supposed to respond to inflammation and so is the beta amyloid. When they get messed up . . . This creates a major problem.

Rashid Deane: Yeah. Well, we didn’t actually show whether copper can actually cause the prion to cause any conformational change.

Shelley Schlender: There are other studies from some time ago that showed that copper binding to a prion changes its shape.

Rashid Deane: That’s right, yeah. (Dean adds that his group has not studied prion disease – just confirmed that copper binds to cellular prions.  His work shows that copper-laden prions bind to LRP1)

Shelley Schlender: You didn’t prove that – it’s been proved by others, but I gather from what you’re saying that you’re assuming that if you get excess copper around these prions without getting it cleared out properly, it can start to mess up how these substances bind with LRP1.

Rashid Deane: It could mess the LRP1 receptors up, definitely.

Shelley Schlender: And when they’re messed up, instead of properly binding to this lower-the-inflammation LP-whatever protein, those mop-up proteins instead start to clog up the receptors so that those receptors can’t do their job?

Rashid Deane: That’s right, they can’t. They get damaged.

Shelley Schlender: Here’s all this stuff trying to happen right in the poor brain, just in the circulation, and the copper binds to the wrong thing, which sets a chain reaction up that leads to the beta amyloids and the prion proteins getting stuck on the wrong side of the blood-brain barrier.

Rashid Deane: Yeah, it gets into the brain and then they can’t get out (at an efficient rate).

Shelley Schlender: Yes, that was fascinating. And also it was fascinating that you—I gather from your paper that you’re saying that it just takes excess copper circulating in the blood to make these things start to go wrong.

Rashid Deane: Yeah, there has to be more copper in the blood of the mice.

Shelley Schlender: There has to be excess copper in the blood inside the brain, and a body that’s not doing a good job keeping the excess copper from going up into the brain, and then these receptors getting clogged up or sluggish for any reason means the body’s in trouble.

Rashid Deane: Yes, that’s right-(Deane adds that the way he would say it, himself, is that this chain of events means that the LRP1 receptor that lets toxins pass out of the brain, through the blood brain barrier, gets damaged) Once the copper level goes up in blood, the receptors that normally clear it from the brain side to the body’s side get screwed up and it can’t work, or it’s clogged up LRP1 receptors.

Shelley Schlender: I think it does sound kind of clogged up. It down-regulates the receptors.

Rashid Deane: Yeah, I’m considering whether clogged up is a good word, because clogged up means it still stays there, but what happens is, it get degraded. Clogged means that it’s blocked and stays there, in a way, so clogging in that way is a good term, because it’s not doing its job any more, for sure, but then what happens is, (Dean clarifies that it’s not just clogged up . . . the binding protein is)  damaged, and when it’s damaged, it’s removed.  But in all of this, the capacity to remove the amyloid from the brain itself, back down through the blood brain barrier, is reduced. It’s like, you know, ferries taking people from one bank of the river to the next bank? If there are fewer ferries, less people can be taken across. The ferry’s damaged and we remove it from service to get it repaired, but in this case we can’t repair it, and it gets broken to pieces.

Shelley Schlender: Or it could be, it’s like on my street if half the trash trucks are broken, then we have a lot more trash pile up.

Rashid Deane: Yeah, [laughs] that’s true, yes. And that’s exactly what happens. The trash piles up on the brain side. You got it right. [laughs]

Shelley Schlender: Are you one of the first people to observe that if this LRP1 protein is down-regulated, there’s more likelihood of beta amyloid build-up?

Rashid Deane: (We’re the first to show that LRP1 can be down-regulated by copper, yes. But down-regulation of LRP has been known for a long time with aging. I’ve worked in LRP before. It’s been known that it’s down-regulated in Alzheimer’s Disease. But the effect of copper on this transport, this is the first time it’s been studied in this way.

Shelley Schlender: And copper has been known for a long time to affect prion proteins, in a bad way?

Rashid Deane: That’s right, in the ’90s, yes. It’s been shown that copper binds to cellular prions and causes a lot of effects. It’s a little bit controversial whether copper is a key culprit for that, but it has been known, for sure.

Shelley Schlender: And I keep wondering, if there is any way that we’ve dumped more copper into our world that we hadn’t before? Deer don’t take copper supplements, and yet deer in Colorado are much more prone to having a brain-wasting disease than they used to be.

Rashid Deane: Hmm.

Shelley Schlender: There are things we don’t know, but it sounds to me like the copper binding . . . 

Rashid Deane: —to the amyloid.

Shelley Schlender: That’s a new idea, isn’t it?

Rashid Deane: Well, it’s not totally new, because as you raised just now, we have known for a long time that the copper attaches itself to the prion and causes conformational change and causes a lot of other things. We also knew that copper binds to another big protein, which is APP, amyloid precursor protein, which is a molecule that gets chopped up into pieces and which produces the amyloid which we see accumulate in the brain in Alzheimer’s disease. So that we know. Our work has shown that once the copper binds to these molecules and causes it to clog up, as you’ve described, it then actually attaches itself to the LRP and causes a bigger clog, because we now have not only the prion binding to the copper and clogging up the system, we have the copper binding to APP and clogging up the system as well. That actually means all these molecules clog up the system that actually clears the amyloid out of the brain.

We see a broader link between the copper and the prion and the APP to this protein that traffics the amyloid out of the brain, meaning LRP1. We actually brought all those together and said that this is contributing to it. We’re not saying that the copper and the prion cause prion disease, because we haven’t worked on that. All the conformation change of prions — That’s a different story. Maybe copper does change them as well. Maybe that’s part of the feature of how they’re clogging up the system, all the conformational structures change and clog it all up.

Shelley Schlender: Well, yes, it could be that. Or it could be that the same way that copper can mess up these proteins is a mishap to look at for among other things that can mess up those proteins.

Rashid Deane: That’s right, yeah.

Shelley Schlender: So glycosylation, if there’s too much sugar gumming up the proteins so that their shape gets messed up, then maybe those caramelized proteins could end up clogging these receptors, too.

Rashid Deane: I think you hit the nail there. We need to think more broadly about all these toxins or substances that could clog up the system, the normal physiological system that we have to handle these toxins in the brain, toxins like amyloid. Perhaps one of these  mishaps in copper processing contributes to it. And there may be a lot more out there. A lot of times the risk factors that might contribute to Alzheimer’s disease are multifactorial, and maybe all of these can contribute. If you were have many of these, maybe the effect is greater.

Shelley Schlender: I know that there has been a lot debunking the idea that diabetes can raise the rate of Alzheimer’s disease, but any condition that glycosylates and sugars up the proteins could be causing some of them to clump onto those receptors in the wrong way, too.

Rashid Deane: You’re right, because in the case of diabetes, there’s another protein “garbage truck,” if you want to call it that, called RAGE (Receptor for Advanced Glycation End Products), and that also handles the traffic of Beta amyloids into the brain, which we’ve worked on in the past. It’s very likely that these things all get affected and operate to transport more of the toxin into the brain, in this case, and may contribute to Alzheimer’s disease. You’re right. I think we need to look more closely at all these toxins in our environment and see what are the impacts on these proteins that cause disease, such as Alzheimer’s disease.

Shelley Schlender: Are you going to look more closely at copper yourself, or will you keep looking for more things that start to mess up proteins in the brain so that they stick to these receptors at the wrong time? 

Rashid Deane: For the near future, a little bit more copper, to try to nail this down a little bit more. I would like to convert our research findings in some way to treatment, to delay the onset of this disease, because this is a horrible disease and we need to find something to deal with it. I’m think, if there’s something we can do, or the public can do, to actually reduce the time of onset of this disease, whatever that is, we should find it so we can start doing it, because we don’t have a treatment around the corner for Alzheimer’s disease. And if we think that copper is contributing to this, maybe we should look at it more carefully, because some copper is good, but too much is bad, so we need to get a balance. And what other things out there come next that may interplay with this whole process? And you’re quite right, there must be several other compounds doing similar things, and maybe we need to find what these are, and maybe the cocktail of these damaging compounds, all together, are even worse.

Shelley Schlender: But you’re not inclined to include the non-steroidal anti-inflammatory drugs in this as one possibility for a compound that could mess things up?

Rashid Deane: That’s being done by others as well, studying anti-inflammatory effects.

Shelley Schlender: But your information would make me think the other way around. Non-steroidal anti-inflammatories, we know that in the short therm, they reduce inflammation and pain, but, in the long term, they mess up knees and cause more pain.  That is, in the short term, they make a knee feel better, but over time they mess up bones and knees through the long-term side effects. I know that you say it’s a different mechanism, but that was intriguing, that this drug, N-acetylcysteine, which clears out an overdose of Tylenol, also helps a clogged up LPR-1 receptor work better. That was interesting.

Rashid Deane: Yeah. But we’re using N-acetylcysteine because it is an antioxidant. But back to your question about anti-inflammatory, we found out in excess copper in the brain, the inflammatory response is actually increased. It’s ok once you have an inflammatory reaction to take an anti-inflammatory, but we are going way back with trying to prevent excess copper, which actually causes inflammatory responses in the mouse model for Alzheimer’s Disease. So we figure maybe we should actually reduce the copper levels or something like that, or control it, fine-tune it, if you like, to a level that is called a beneficial effect. Because the current belief I have of it is that too much of it will be bad, but too little will be bad as well, so we have to get a balance. We have to know where that balance is. Right now I don’t think we have a clue yet. But we know too much copper is bad because of this sort of work, and other work out there as well, as I indicated. It’s that controlling the things that cause it initially is far better than actually controlling the effect of this later on downstream. If copper is causing the inflammatory response, we can always treat the inflammatory part of it, but if the things that are causing it are still there, all you will have is more and more of it.

Shelley Schlender: So you’re suggesting that the EPA be more strict about copper levels and that people watch their vitamins more carefully and make sure they don’t take a little bit of copper here and there and have it add up to too much?

Rashid Deane: If you’re already having a good balanced diet, like having nuts, vegetable, fruit, cereal, these all contain lots of copper in them, so maybe we already have enough. There’s some in the water as well, and maybe we don’t need copper supplements. Maybe we can take another supplement, like fish oil, instead. But if we actually religiously eat a good diet because we know it’s good for us and we’ll do that, we think, “Oh, well, we must take supplements as well, because it’s good for us,” so we take all these supplement tablets with loads of vitamins and minerals, and they also have more copper than we’re already taking, I could see a stage where somebody is very clear in health issues, doing all of this because they think it’s good, and then they go overboard, too much. And we definitely don’t want to prevent people from taking copper, because it’s important, and if you weren’t eating all the nuts and the vegetables and the fruit, maybe the supplements are very good, because they have about 2 milligrams in them, roughly speaking, of copper, which is actually essential.

Shelley Schlender: And definitely don’t do things that mess up your blood-brain barrier clearing out the copper, either.

Rashid Deane: No, we should minimize that, actually. Maybe we should take more antioxidants in our food to try to protect the oxidative damage that we cause in our blood-brain barrier, because that’s what’s contributing to it with our aging, and then maybe if we do that a little bit more, we may delay this whole process. The blood-brain barrier may be intact for a longer time, and if it is, maybe some of these effects are delayed. We achieve something by delaying the onset of diseases as a whole, and Alzheimer is one of them. I’m talking Alzheimer’s because it’s close to my heart, but I think it’s good for other diseases as well. And I think one day, just as we have preventive measures for cardiovascular disease, we always say, “Do this, do this,” if we lower our blood pressure we reduce our chance of getting a heart attack, I hope one day we can say the same thing for Alzheimer’s disease, and I hope that comes quickly. “Take this, do that,” and we can delay the onset of the disease. And maybe this is one part of it.

Shelley Schlender: Are you of the camp that thinks that beta amyloids are always bad, or are you thinking more than beta amyloids serve an important function?

Rashid Deane: I think beta amyloid plaques must be serving something. We don’t know precisely what, but I think too much of it is bad. The increased accumulation of amyloid plaques is definitely associated with Alzheimer’s disease.

Shelley Schlender: But are you in favor of melting the amyloid plaques, or you thinking they might be protective?

Rashid Deane: The amyloid that’s deposited in the brain? [laughs]

Shelley Schlender: I’m thinking of the salmon. (That’s a line of research done by CU scientists who include Tammy Maldonado, and it points out that in the salmon, the accumulation of beta amyloids in the brain may be protecting key areas of the brain from a cascade of damage in the final stage of the salmon’s life)

Rashid Deane: Yeah, the salmon. I think the amyloid, I think too much of it is bad. I don’t think we should have a lot of amyloid in our brain. The amount that’s deposited in the brain as amyloid when we see it in Alzheimer’s disease, that’s not good for us. In its free form, where it actually is part of a healthy physiological condition, like you and me right now, we are producing this protein amyloid, but we are clearing it very quickly, so it’s not accumulating in our brain. You asked the question about what it’s doing, what’s its function? We actually don’t know all the details of what beta amyloid does normally. It may well have a protective effect as well. I mean, there are people who think it’s deposits from clogged-up vessels that are leaking, some don’t believe that’s the case.

Shelley Schlender: Some people think beta amyloid plaques that accumulate in the brain are a band-aid for bigger problems that would be happening if the plaque wasn’t there.

Rashid Deane: That’s right. Maybe that’s what it does in some places in the brain as well, but when you have too much of it, it becomes bad, because if we have too much of this band-aid wrapping around the blood vessel, the vessels can’t do their job. They can’t expand and contract normally to cause things to flow. If you have a band-aid on one part of your skin, it might be all right. But if you wrap that around too much of it, maybe it’s not going to be good to have too much band-aid around, and for too long.

Shelley Schlender: And most of all, you think it’s important to figure out what’s causing the band-aid to be there in the first place, what’s causing the problem that means the beta amyloid plaques are accumulating. And between copper and this down-regulation of this receptor that lets toxins out, you think there’s something there to figure out?

Rashid Deane: That’s right. Thank you very much.