How a key Alzheimer’s gene wreaks havoc in the brain

Host: Benjamin Thompson

Welcome back to the Nature Podcast. This week: a genetic link for late-onset Alzheimer’s.

Host: Nick Petrić Howe

And updates from the ground at COP27. I’m Nick Petrić Howe.

Host: Benjamin Thompson

And I’m Benjamin Thompson.

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Interviewer: Benjamin Thompson

Before we start the show, there’s something I’ve always wanted to be able to say, and that is, ‘We interrupt this broadcast for a late breaking story.’ And that story is the first launch from NASA’s Artemis programme, which happened about an hour ago, very early this morning as I record this, well after the show is normally put to bed for the week. It is a story, of course, we wanted to include in the show, so I set multiple alarms to make sure I didn’t miss it, and watched along with Alex Witze, who’s been covering the Artemis programme for Nature, and who joins me on the line now. Alex, the launch happened at 1:47am ET in the US – you must be exhausted.

Alex Witze

I am, but that was just amazing, right? To see this incredibly huge rocket soaring, and at night too, a night-time launch from Cape Canaveral in Florida. So, just this giant pillar of flame, so much bigger than what we’re used to seeing with other rockets, even from the days of the space shuttle, from the Falcon launches that we see these days from SpaceX, just a pillar of flame rising. That was just amazing.

Interviewer: Benjamin Thompson

Well, let’s break it down then. So, NASA is now in the Artemis era, and today saw the launch of the Artemis I mission. But when we talk about the Artemis rocket, let’s make sure we know what we’re talking about because there’s actually two separate things being tested here, right?

Alex Witze

Yeah, so, what happened today is it was the very first time NASA has launched this enormous rocket called the Space Launch System, which is meant to bring people back to the Moon for the first time since the Apollo era, and it's carrying a capsule called Orion. So, to get people from Earth to the Moon takes an enormously powerful rocket, and so today's launch was to test that. So, it's an end-to-end test, brand new rocket, capsule it’s carrying, the whole system, the whole package.

Interviewer: Benjamin Thompson

So, to be clear then, today was an uncrewed mission then.

Alex Witze

Today was a test, yes. There was a Shaun the Sheep doll. There were some mannequins. There were no humans onboard today.

Interviewer: Benjamin Thompson

I mean, obviously a successful launch, but getting here has been a bit of a struggle. August 29 was the first attempt to get this Artemis I mission off the ground. But of course, there's been a lot that's gone on before then and subsequently, up until today.

Alex Witze

Yeah, this entire story has very, very deep roots in NASA trying to figure out a way to get back to the Moon. Not just since August but really since decades it's been looking to build a way to get back to the Moon. So, they've been working on this very large rocket for a very long time. They have put all the components together, tested it in various ways. And then the question was, when were they going to launch it? Years ago, they thought they were going to launch it in the late 2010s, then it sort of just kept pushing out. And then earlier this year, they thought they were going to fly for the first time. That got delayed for various reasons. In August and September, some hardware problems at launch. Then there were two hurricanes on the launchpad that delayed it further, but it got up tonight.

Interviewer: Benjamin Thompson

And there were some concerns with the last obviously devastating hurricane that actually some parts of the craft fell off.

Alex Witze

Yeah, this is a pretty badass rocket. I don't know if I can say that on the Nature Podcast. But it literally went through a hurricane a week ago. There was one hurricane where they rolled it kind of back into the garage, but then there was a second hurricane where they just left it out on the launchpad, basically because they ran out of time to roll it back. And it had some damage. And I have to say a number of us were quite sceptical that it wasn't going to be damaged more. Perhaps there's unseen damage we haven't seen yet in this flight. But it seems to have weathered it okay.

Interviewer: Benjamin Thompson

Well, let's talk about what happens next then. So, obviously, we've had the launch, but that's part one of a multistage process.

Alex Witze

Yeah, you and I are talking right now. The rocket has launched successfully. It has put this capsule into orbit around Earth. And at the point that we're talking here, we're waiting for it to do – this is like terminology from the Apollo days in the 60s – what's called a translunar injection burn, basically the burn to get it on the path to the Moon. That hasn't happened yet but it should happen in the next hour or so. And then this capsule will go sort of around and behind the back of the Moon. And it's going to go very close to the Moon surface – as close as 80 miles – and kind of do this looping orbit around it for 26 days, if everything goes well, and then the plan is it will return to Earth and splashdown off the coast of California.

Interviewer: Benjamin Thompson

And I mean, while this is clearly a test mission, the first mission, there is actually some science on board. What can you tell me about that?

Alex Witze

Yes, there's a bunch of different science that's going to be done. For one thing, Artemis I is carrying a bunch of little satellites that will throw out and do science. Some of them will go map water on the Moon, which is kind of a big thing right now. But also, on the capsule itself – this thing that's designed to carry astronauts in the future – there's experiments that look at radiation in deep space and how harmful is it to astronauts? How dangerous is it to be flying through deep space where there's all this radiation, galactic cosmic rays, solar particle events, that kind of stuff? There are two mannequins, one of which wears this protective radiation vest, one of which does not. They're both in the female form. So, one of the things about Artemis is Artemis is named for the Greek goddess who is the twin sister of Apollo. One big theme of the Artemis programme is to fly female astronauts to the Moon for the very first time. We've only had men walk on the Moon to date. And the idea is to see can these protective vests help protect women who are more vulnerable to radiation as astronauts?

Interviewer: Benjamin Thompson

I mean, you're talking about the future there, Alex, and of course today is very exciting. But people will already be thinking about the next steps, right, Artemis II, Artemis III. When can we maybe expect them and what will they be doing?

Alex Witze

So, Artemis II will be like the flight today, but it will have humans on it. So, it'll be the first crewed flight. It will have four astronauts on it and it will loop around behind the Moon, just like Artemis I, fly around for a while but not land, and then come back to Earth. Artemis III is the really big one. That will be the landing. So, NASA plans to put astronauts into Artemis III and fly it to the Moon and land at the Moon’s south pole. And this would be the first time that humans return, as far as NASA is concerned, since Apollo 17. When all this happens? That's a great question. It all comes down to money and technology and all that stuff. But NASA is talking theoretically about Artemis II in 2024 and potentially landing on the Moon in Artemis III the following year, 2025.

Interviewer: Benjamin Thompson

I mean, you mentioned costs there, Alex. And I think it's worth talking about because the figures involved for the Artemis programme in general and for each mission are absolutely staggering.

Alex Witze

US$ 4 billion a flight is the estimated number. That's a lot. And these rockets are not reusable, right? So, they sort of burn up and a lot of the components just fall into the sea and are not reusable. And yeah, you need a lot of money to make that happen.

Interviewer: Benjamin Thompson

But putting that to one side, what do you think today means for NASA and for space exploration? I mean, lots of companies are entering the space game now, and in many cases launching or aiming to launch smaller, bespoke rockets and missions, certainly in terms of Moon exploration. And here is NASA with a rocket that is 100 metres tall. Is it a statement of intent, do you think?

Alex Witze

It’s all about humans and our experience in the cosmos, right? Because there are many, many nations and even private companies now that are going to the Moon, but they're sending robots, they're sending little landers to do stuff on their own. Today was all about human exploration, and can we, as a species, go back into space and take those next steps to move deeper into the Solar System? So, think about it, it's been 50 years since astronauts came back from the Moon. And since then, NASA has focused on, first, the space shuttle, just kind of going up and going around Earth and coming back, and then also living and working aboard the space station, which is also in Earth orbit. So, we haven't gone beyond kind of our cosmic neighbourhood in many decades. Today was all about opening that door again, sort of pushing out of that neighbourhood, going to the next place over, and seeing can we move beyond our own little realm, not as robots. As humans, can we do this?

Interviewer: Benjamin Thompson

And obviously, you've spoken to multiple scientists, engineers, and so forth. What have they been saying about all that’s been going on?

Alex Witze

Yeah, I mean, scientists, as well as a lot of other people, have pretty complicated feelings about this, right? A lot of lunar scientists really just want to go to the Moon and get rocks, and it would be great if we could have astronauts picking up the rocks and bringing them back because there's many, many scientific secrets you can get. The history of the Solar System, the history of Earth, all sorts of information is contained in the Moon that we don't have here on Earth scientifically. But it is expensive. We have a lot of other priorities. Our own planet has its own pressing needs. So, many scientists are very into human exploration of space. Others advocate for robotic exploration or say we should be spending time and energy on our own planet. But no matter what you think about that, I think today's launch, it's going be pretty pivotal in how people think about our place in the Universe again because we just haven't had that access to space in a very long time.

Interviewer: Benjamin Thompson

Well, Alex, what a moment indeed. Thank you so much for joining me today.

Alex Witze

Thanks for having me.

Interviewer: Benjamin Thompson

Alex Witze there. And for all the latest updates on the Artemis I mission, look out for links in the show notes.

Host: Nick Petrić Howe

Coming up, we’ll be hearing the mechanism of how a specific gene may be implicated in late-onset Alzheimer’s. Right now, though, it’s time for the Research Highlights with Shamini Bundell.

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Shamini Bundell

When it comes to scoring goals, the success of a football team doesn’t just depend on sporting skills. Research on things like kit can also improve the safety and performance of players. But most pieces of sports tech are optimised for men. A new report shows that elite women’s football still has a long way to go before it matches the men’s game when it comes to specifically tailored equipment. It highlights how so-called ‘unisex’ football boots actually don’t fit women that well, and can even reduce performance and cause injury. There are also unknown health impacts of women’s teams playing with footballs the same size and mass as the men’s teams. Professionals also often have to wear sponsored kit, which may not have an optimum sports bra for their build, again affecting performance. The authors highlight a lack of research in this area. A lot more work is needed, it seems, to really level the playing field. Dribble on over to the journal Sports Engineering, for more.

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Shamini Bundell

Stromatolites – these layered formations are sometimes considered oldest evidence for life on Earth, as they could have been made by mats of ancient microorganisms. But proving that they were formed by biological and not simply chemical processes hasn’t always been easy. Now, a team of scientists has taken two- and three-dimensional images of the microstructure inside some stromatolites from Australia. One of the significant features they found were dome-like shapes. These are very similar to structures made by modern photosynthetic microorganisms as they grow towards the Sun. The researchers say these findings make a convincing case for a biological origin – for these particular stromatolites at least. As well as being a fascinating glimpse of early life, this work could also aid the search for life on other planets. The conditions that the Australian stromatolites formed under are likely very similar to the environment on the edge of the Jezero crater on Mars, billions of years ago when there was an enormous lake there. The techniques used to analyse these rocks could also be applied to Martian specimens in the future. Find the full paper in the journal Geology.

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Host: Nick Petrić Howe

The main risk factor for Alzheimer's disease is age, but it's known that a number of genes also play a significant role. However, it's not been quite clear how they do so. Now, reporter Ali Jennings has been looking into a new paper that might reveal how one of these genes is involved in Alzheimer's.

Interviewer: Ali Jennings

There are an estimated 50 million cases of Alzheimer's disease every year, and between 50-80% of the more common late-onset variety of Alzheimer's disease is inherited. It stems from genetic variation. The gene most strongly associated with late-onset Alzheimer's disease is called Apolipoprotein E, or APOE for short. And it's the APOE4 version of the gene that's the major risk factor. And yet, despite APOE4’s importance in causing late-onset Alzheimer's, it's still unclear how it actually does so.

Interviewee: Li-Huei Tsai

So, we figure that if we can understand how APOE4 causes Alzheimer’s disease, then we will really make significant inroads in terms of understanding the pathophysiology of this very devastating disease.

Interviewer: Ali Jennings

This is Li-Huei Tsai, an Alzheimer's disease researcher from MIT. Li-Huei and her lab have been working on APOE for around ten years now. APOE encodes proteins that regulate the transport of fat molecules called lipids. But studying this particular gene is not easy.

Interviewee: Li-Huei Tsai

There are many different kinds of lipid, and different cell types usually have different cell-type-specific pathways regulating lipid metabolism. And lipids play different roles in different cell types. So, it's just extremely complicated to deal with.

Interviewer: Ali Jennings

So, to unravel how APOE was working in Alzheimer's, Li-Huei and her team had to turn to a number of different but complementary techniques. First, they took samples of human brain post-mortem and measured how different brain cells expressed genes when they carried APOE4, and one particular kind of brain cell stood out – oligodendrocytes.

Interviewee: Li-Huei Tsai

In oligodendrocytes, what we see is a very marked increase in cholesterol biosynthesis pathways, and that really caught our eyes because cholesterol biosynthesis is not known to be so active in oligodendrocytes. So, we were very curious to know what's going on there.

Interviewer: Ali Jennings

Oligodendrocytes use cholesterol to make insulating sheaths around neighbouring neurons made of myelin. This myelination is important to allow neurons to fire properly. Under the microscope, it shows up as a ribbon-like structure.

Interviewee: Li-Huei Tsai

In the APOE4 carrier’s brain, this kind of nice, ribbon-like cholesterol structure along the axon is diminished and instead we kind of saw cholesterol sort of signal closer to the cell nucleus. So, the localisation of cholesterol seems to be abnormal in the brain.

Interviewer: Ali Jennings

Not only is the cholesterol abnormally located within the oligodendrocytes, but it also seems to decrease the activity of genes involved in myelination. So APOE4, by messing with cholesterol, seems to be linked to neurons having damaged myelin sheaths. This could decrease the speed of transmission between neurons, which might explain some of the cognitive deficits seen in Alzheimer's. Now, Li-Huei had evidence that APOE4, when expressed in oligodendrocytes, raised their cholesterol and inhibited their myelination. So, the next question was, what could she do about it?

Interviewee: Li-Huei Tsai

So, we want to find a way to see if we can reduce this accumulation of cholesterol inside the cells, whether we can rescue myelination.

Interviewer: Ali Jennings

So, the team turned to a mouse model of Alzheimer's disease. They tried a number of drugs known to regulate cholesterol synthesis, including statins, but saw no effect. So, instead, they tried a drug that promotes cholesterol transport – cyclodextrin.

Interviewee: Li-Huei Tsai

And there, voila! We saw a significant decrease in the cholesterol accumulation inside this APOE4 oligodendroglia. So, we treated these mice with cyclodextrin for 2-3 weeks, and then we saw the rescue of myelination abnormalities. But furthermore, these animals perform better in a couple of memory tasks.

Interviewer: Ali Jennings

And so, the obvious question then is, could this drug have therapeutic potential?

Interviewee: Li-Huei Tsai

It has potential, yes. I will say this series of observations are very exciting.

Interviewee: Karl Carlström

But like the most fascinating thing is, I think, that they can actually have certain gene variants. So, in this case, APOE4, and that they can actually translate that into a dysfunction in these cells and like show a possible mechanism of how this is working and how that mechanism is related to a risk gene for Alzheimer's disease.

Interviewer: Ali Jennings

This is Karl Carlström from the Karolinska Institute in Stockholm, who has written an expert review of the new study. He's enthusiastic about the work.

Interviewee: Karl Carlström

And another thing that is also like interesting is that they see this behaviour with accumulating cholesterol in the Alzheimer's disease-diagnosed patients, but they also see this accumulation in undiagnosed patients. So, it could well be that, okay, this is a mechanism that appears prior to clinical onset.

Interviewer: Ali Jennings

If this APOE4-linked myelination defect appears before clinical diagnosis, that might indicate this is part of the root cause of Alzheimer's disease rather than an exacerbating factor. But as well as being excited by the findings, Karl says there are some things still to be clarified. For example, the protein APOE codes for can be trafficked out of the cell where it's made, and affect other nearby cells. Li-Huei has shown that the myelination problem stems from APOE4 specifically in oligodendrocytes, but Karl notes that it's possible the APOE protein could actually be working by targeting neighbouring neurons, which then feedback to trigger the effects in the oligodendrocytes. That's one route that future work could go into. But Karl thinks that this work also opens up many other new avenues to explore.

Interviewee: Karl Carlström

How can this contribute to pathology in general? Is this something that is appearing in other diseases? We don't know.

Interviewer: Ali Jennings

On the other hand, Li-Huei is thinking about what this means for Alzheimer's disease more broadly.

Interviewee: Li-Huei Tsai

Whether this kind of lipid disruption is a general mechanism underlying the pathophysiology of Alzheimer's disease, I'm very curious about this question.

Interviewer: Ali Jennings

And Li-Huei feels that this work has opened her eyes to APOE4’s pervasiveness in the brain.

Interviewee: Li-Huei Tsai

You sort of feel that APOE4 cannot escape you now. You kind of see the fingerprint of APOE4 on every cell type. That is extremely exciting for me.

Interviewer: Ali Jennings

So, perhaps in the future, we'll find more clues to uncover the mystery of Alzheimer's disease, with APOE’s fingerprints all over them.

Host: Nick Petrić Howe

That was Ali Jennings. You also heard from Li-Huei Tsai from MIT in the US, and Karl Carlström from the Karolinska Institute in Sweden. To find out more about this story, check out the paper and the News and Views article written by Karl in the show notes.

Interviewer: Benjamin Thompson

As we talked about on the show last week, COP27, the UN's Climate Conference, is underway in Egypt. And to get a sense of what it's like at the conference this year, I'm joined by Flora Graham, senior editor of the Nature Briefing who is at the event. Flora, thank you so much for joining me today.

Interviewee: Flora Graham

Thanks so much for having me, Ben.

Interviewer: Benjamin Thompson

So, then, we're recording this on Tuesday. What's the mood like at the conference?

Interviewee: Flora Graham

Well, we're really in the thick of it now. I mean, a lot of people have been hard at it for a week already, and a week of late nights and conference sandwiches will tire anyone out. So, I would say there's a feeling of being in the dark forest of the narrative at the moment. But as always, the negotiators and the participants do come ready for long days. And I would say on the conference floor, there's still a lot of energy, especially in the youth pavilion. I walked in there today and I just felt, wow, this is where the magic is happening. There was a lot of chatting and smiling and laughing, and the energy is definitely still there.

Interviewer: Benjamin Thompson

Which is interesting to hear because there's been reports of perhaps a mood of uncertainty, given the slowness of how some of the negotiations are going.

Interviewee: Flora Graham

It's hard to say at this point because I think there's always a feeling of uncertainty at this point, and I think that will continue right up to the end, to a certain extent. But I think that part of the uncertainty is coming from some of the issues that this COP is dealing with, which are very different from last year's in Glasgow. Loss and damage, which we know has now been added to the agenda, dealing with questions of implementation, legislation, oversight, reporting. These are not necessarily glamorous topics, but they're absolutely essential. And then even beyond the walls of the conference itself, thinking about the human rights issues that have been raised over and over with regards to Egypt’s hosting of the event. So, I think that adds to a certain feeling of maybe tentativeness because everybody is very aware that we're kind of walking very gingerly through some difficult areas.

Interviewer: Benjamin Thompson

And what about the sort of conference setup itself then? You were in Glasgow for COP26 – how does this one compare, maybe?

Interviewee: Flora Graham

I mean, some key differences are like, obviously, it's hot and it's in a desert, so we're sitting in the highly air-conditioned buildings. A lot of these are temporary structures with very thin walls, they're huge aeroplane-hangar-sized buildings, and it does really create a bit of a jarring effect on the ground. But one big difference is, whereas in Glasgow the booths were very much kind of segmented, so there might be an area that was majority country booths, there might be an area that was majority kind of private sector or non-governmental organisations. Of course, there was a little bit of a mix. But here, it's really all mixed up. So, you've got activists, right next to companies, right next to countries. And it's interesting because it does give a little bit of a different feel. In some areas, it feels a little bit less utopian because you don't have this kind of parade of nations aspect. But the exhibitors I've talked to have not found that in any way detrimental. Most of them have said it's kind of just another COP once you get in through the doors.

Interviewer: Benjamin Thompson

And what about the news that's coming out, Flora? What should we be keeping our eyes and ears out for in the forthcoming days?

Interviewee: Flora Graham

Well, one of the topics that I'm going to be writing about today in the Briefing is really about this idea of the 1.5 °C. Now, this is the Paris target to keep the increase in global temperatures below 1.5 °C above what it was before industrialisation. And this has always been an aspirational goal, but nevertheless an extremely vital goal in terms of keeping some of the absolutely worst aspects of climate damage at bay. Now, the debate today and the last few days between a lot of people is, there's been a lot of data suggesting that 1.5 °C might be out of reach, that we've already put too much carbon in the atmosphere and we're not on track to make the cuts required. We're certainly nowhere near any kind of carbon sequestration technology or anything like that, that would turn that around super quickly. So, there's an argument that if 1.5 °C is out of reach, we should perhaps grasp the nettle, accept that and really kind of double down our efforts on understanding what that means and what kind of mitigation and adaptation strategies might be necessary. Now, other people are absolutely diametrically opposed to that and then are saying that letting go of 1.5 °C is a huge mistake and it's equivalent to giving up, and it's equivalent to saying that some of these terrible effects of climate change are acceptable, and that we must absolutely pursue 1.5 °C and even redouble our efforts or recommit to that very ambitious target.

Interviewer: Benjamin Thompson

Flora, there’s been a lot of talk before and during the COP27 conference about journalistic freedoms and things like that. What have you experienced now you're there?

Interviewee: Flora Graham

At the moment, we're living in that parallel world. I mean, Sharm El-Sheikh is already a bit of a parallel world within Egypt. It's a place that is built for tourist dollars to come in. It's quite far from Cairo. And I think there's a feeling that is often able to be maintained in these kinds of countries where there's kind of two levels. There's a level that's presented to the outside, and there's a level that's able to be maintained in a certain way, and that's the one we're able to operate in. And I feel completely free to do as I like and say as I like within this conference, and then there's what might be going on outside these walls and outside Sharm El-Sheikh. So, I think the difficulty for us as journalists is how do we participate in this conference in a way that gives our readers the very important information that they need without acting as a smokescreen for the things that are happening in Egypt that are not to be swept under the rug, in terms of human rights abuses and individual freedoms and press freedom. So, that's a bit of a tightrope to walk and that’s one that we're going to do our best to face up to as honestly and directly as we possibly can.

Interviewer: Benjamin Thompson

And finally, then, Flora, you're at COP until the end of the conference, working on the Nature Briefing, of course, and you've been asking for readers to get in touch. What are you looking for?

Interviewee: Flora Graham

It's important to us that we answer the questions that our readers have. And we will always dig deep into the science and how science influences these kinds of policy meetings, but we are very keen to hear any specific questions that our readers might have, any particular angles that they're very interested in. And I hope that they'll email me at briefing@nature.com and tell me what they want to read about.

Interviewer: Benjamin Thompson

Nice one, Flora. Thank you so much for joining me today.

Interviewee: Flora Graham

Thank you so much.

Host: Benjamin Thompson

Flora Graham there. For the latest on what’s been happening at COP, look out for links in this week’s show notes.

Host: Nick Petrić Howe

That’s all for this week. As always, you can keep in touch with us on Twitter – we’re @NaturePodcast. Or you can send us an email to podcast@nature.com. I’m Nick Petrić Howe.

Host: Benjamin Thompson

And I'm Benjamin Thompson. Thanks for listening.