Podcast – AAIC 2020 – Day One

Voice Over:

Welcome to the NIHR Dementia Researcher podcast, brought to you by dementiaresearcher.nihr.ac.uk, in association with Alzheimer’s Research U.K. and Alzheimer’s Society. Supporting early career dementia researchers across the world.

Dr Megan O’Hare:

Hello everyone, and thanks for joining us, I am Megan O’Hare and I am delighted to be hosting our first daily Alzheimer’s Association International Conference special podcast. So we’ll be sharing news and our favourite moments from each day of the AAIC, like we do normally but as you probably know, the conference was due to take place in the Netherlands this year, but the pandemic has changed all that, and so this year’s conference is taking place virtually, with every talk and poster still being shared online, and there are live scientific sessions and pre-recorded and on-demand videos as well. I imagine a lot of you have registered because I think they had over 20,000 registrants, which is a lot of people. And I think it’s all worked really well, I think we can say that it’s all worked really well, I know yesterday there were a couple of problems with probably bandwidth situations where some of the slides were a bit blurry for the live sessions, but they’re going to be available online soon so then you’ll be able to see properly.

Dr Megan O’Hare:

So yeah, I think shall we move on to introductions? I’m delighted to be joined by Dr. Lindsey Sinclair, psychiatrist and post-doctoral researcher over in Bristol. Dr. Emily Maguire, a research associate from Cardiff University, and Professor Louise Serpell who is professor of biochemistry and Director of Neuroscience based at the University of Sussex. So I’ve interviewed a couple of you, don’t think me and Emily, we haven’t met yet, but very excited to. So maybe we can start with a tiny introduction from all of you so get a bit of your background and what you’re working on right now. Shall we start with Louise? Because you’re top of my screen.

Professor Louise Serpell:

Hello, hi Megan, thanks for the introduction. So I’m one of the directors of Sussex neuroscience and I work on, a sort of a mixture of structural biology and cell biology to try and understand the causes of Alzheimer’s disease. So yesterday’s AAIC was pretty much my area and it was exhausting in terms of trying to watch just about every talk I possibly could. So I really enjoyed it, I mean it’s really amazing and it’s very similar to the sorts of things I’ve been doing. So there was some amazing panel discussions which I’ll talk about a bit later on.

Dr Megan O’Hare:

Yeah, we sort of mentioned before we started recording that they’d put all the basic science ones on yesterday, and that meant that you had to pick possibly between two or three favourite ones. But I think they are all going to be up online again, so we’ll be able to catch up during the week. So Lindsey?

Dr Lindsey Sinclair:

Thank you very much Megan, so I work at the University of Bristol and I’m an Alzheimer’s Society-funded junior fellow there, which means that I’m a post-doctoral researcher as well as being a psychiatrist. I’m not really doing any of that at the moment because I’m on maternity leave, so from a perspective of a slightly workaholic, working mother, the virtual conference is brilliant. And I think it makes it much more accessible to those of us who may have a few childcare issues, particularly during this pandemic. So I loved yesterday.

Dr Megan O’Hare:

I think we did a podcast right at the end of your pregnancy, maybe at the 38 weeks I think, so-

Dr Lindsey Sinclair:

Yeah, he was born three days later.

Dr Megan O’Hare:

Yeah. So hopefully we won’t have any of that today. But yeah, I think having it virtually has really opened it up, well I mean they’ve had 20,000 registrants so that’s just been amazing really. And Emily?

Dr Emily Maguire:

Hello, so I’m Emily and I work in Cardiff in the Dementia Research Institute, I’m also really happy that it’s virtual this year, I mean it was nice to L.A. last year but it’s also really nice to listen to talks in your pyjamas, as many coffees as you want. So I work, I use human stem cells and I differentiate them into microglia to study Alzheimer’s. So at the moment I’ve got two projects on the go, one is to investigate the effects of the PLC-gamma-2 mutation that is shown to protect against Alzheimer’s, and the other is to try and generate high and low genetic risk models of Alzheimer’s using blood samples from patients who have high and low genetic risk. So making them into stem cells.

Dr Megan O’Hare:

I caught something on Radio Four the other day about Toast, you know the Nigel Slater book? That I’ve never read, but apparently it’s very good, anyway then they did a stage play of it and now they’re doing a radio play of it, and part of it is, if you go to the stage play they give you Walnut Whips and biscuits throughout so that you can eat them while you’re listening to cooking things and stories but now they’re doing it virtually, if you buy a ticket they send you a Walnut Whip in the post, and I did think AAIC should have sent us some biscuits for the coffee break bit, because it’s nice to make your own cup of tea but a free biscuit would have really topped it all off. Anyway, so if anyone’s listening, for next year maybe. Free biscuits.

Dr Emily Maguire:

It would have to be like over 20,000 free biscuits though, that would have been quite-

Dr Megan O’Hare:

Quite a lot of biscuits, okay fine. I’m just going to go out and buy some biscuits later. So okay, shall we start with the plenary session which was delivered by Ralph Nixon on proteostasis failure in Alzheimer’s disease and related dementias, and new clues to pathogenesis and therapy. And Louise, this is really very much your field so do you want to give us a quick summary of the talk?

Professor Louise Serpell:

I will, if I start to go into too much detail and get a bit too excited about it then do just sort of wave at me too much, but basically so Ralph Nixon is from NYU and he’s a very well-known name as you were saying Megan that you remember having referred to his work a lot in your thesis, and his work is really focusing on autophagy, so if you mention autophagy then he’s the name that comes up. And just to say a little bit about what autophagy is, sometimes people pronounce it differently, it’s a biological mechanism of clearance of unwanted proteins, organelles, and it’s generally thought to be a good thing, so it’s a protective mechanism and it generally correlates with longevity and lifespan and it’s intrinsically linked with the endosomal-lysosomal system so many proteins that have been highlighted as being really important in Alzheimer’s disease from GWAS studies and so on, are endosomal-lysosomal proteins so it really highlights how important it is in Alzheimer’s disease.

Professor Louise Serpell:

And what they also noticed is that lysosomal storage diseases show neurodegenerative symptoms, so it suggests that there’s something about lysosomal system that’s really important in the brain. So Alzheimer’s researchers have observed large membrane-bound compartments that suggest that there’s a failure of this autophagosomal mechanism. So really that’s what he talks about, that’s really what he’s been doing for many years, and he mentioned that the autophagy system is tightly regulated by insulin-signalling pathway and mTOR which also then links it back to lifespan and longevity which is really interesting I think.

Professor Louise Serpell:

And he showed that if you can inhibit lysosomal function then you recapitulate AD-type pathology. And what he really talks about in terms of new findings was that he described a fluorescent system where they’d used an RFP and a GFP, which allowed them to follow the auto-lysosomal maturation to follow acidification, so it responded to the PH of the environment which was really interesting for me because we’ve done something similar that a post-doc in my lab, Karen Marshall, published on recently. So that was really nice. And what they noticed is that it looks like, in Alzheimer’s disease, the lysosomal system is not properly acidified.

Professor Louise Serpell:

So there seems to be something that’s going on in the lysosomal system that means there’s a failure so then there’s a build-up of all of those undegraded proteins, many of which are things like A-beta and possibly tau as well, and he showed this really beautiful image of a cell that then became filled with these lysosomal things, and they got bigger and bigger and bigger over time, and eventually the cell looked like it was no longer there at all, and it was just a sort of, well it looked like a plaque actually, an amyloid plaque with a little nucleus in the middle. So essentially it sort of explodes out of the cell, so I just thought that that really nicely showed how important lysosomes are and how the amyloid plaque is generated in general.

Dr Megan O’Hare:

Yeah I enjoyed him saying that lysosomes used to be considered the most boring organelle in the cell and now they’re one of the most interesting because as you said, loads of genes from GWAS studies have centred on that endosomal-lysosomal axis and then he had a list of so many neurodegenerative diseases, I thought that was really interesting.

Professor Louise Serpell:

So the main thing I think at the end of it was really that this was a possibility for targeting for therapeutics, so that’s what he really left us with, that idea that we can try and enhance the lysosomal system to try and produce therapies.

Dr Megan O’Hare:

Yeah, the tool that he used that you mentioned, the fluorescent system as I understood it, it basically fluoresces green when it’s the correct acidity, is that right? And then it quenches to red, or it that it quenches to red as it gets more acidic as you go through the different vacuoles the lysosome sort of becomes more acidic, so if it doesn’t it stays green, is that right?

Professor Louise Serpell:

I think that that’s right. Yeah, green to red I think is the order

Dr Megan O’Hare:

Yeah, that’s the way you want it to go to know that you’re, yeah.

Professor Louise Serpell:

Yeah, so we used a similar sort of system where we tagged A-beta with a sypher label and it just gets more and more red as it goes through the acidification system. So you can follow A-beta as it goes into the lysosomal system and ends up-

Dr Megan O’Hare:

Do you do that live, and track them?

Professor Louise Serpell:

Exactly. So you get a little movie of it all going in and getting brighter and brighter and brighter. And then it’s interesting that it just sort of stays there, and it also seems to impair the lysosome system for other proteins, so if you add a different protein in to the cellular medium, normally it would be taken up by lysosomes and degraded, sorry, taken up by endosomes and then lysosomes, but it seems that whole seems to be impaired. So it’s not just that you get lots of accumulation of protein in the lysosomes and autophagosomes, but the whole system seems to stop working, so the cell doesn’t really function as it should. So it’s quite, I think it’s cool. Yeah, and then there are lots of other talks that seem to sort of come into that so I can always go back to them later. Yeah.

Dr Megan O’Hare:

Yeah, Emily or Lindsey, did you also attend the plenary?

Dr Emily Maguire:

Yeah, and actually so it’s funny that you said that lysosomes were always boring because they’ve always been my favourite organelle, because I did my PhD on lysosomes and on lysosomal diseases specifically. And I guess it’s funny, he did briefly mention it but the real overlap between lysosomal diseases, especially one called Niemann-Pick Type C and Alzheimer’s disease often it’s actually called childhood Alzheimer’s disease because you get storage of tau and amyloid in the brain, and you get a similar-ish neurodegeneration and the loss of lysosomal function and progressive storage. So I think the overlap and the importance of the lysosome in Alzheimer’s disease is key, and clearly his contribution to the field is just immense. Definitely.

Dr Megan O’Hare:

And this all centred on lysosomes in neurons, a new study, microglia, I’m assuming there are lysosomes in microglia, are they affected in any way? Is it a similar situation in glial cells?

Dr Emily Maguire:

I think that, yes, probably, but I don’t know specifically because actually since I’ve switched and working on Alzheimer’s disease I haven’t done that much looking at the lysosome but yeah there are lysosomes present in all cells and I think the function will definitely be affected in microglia as well.

Dr Megan O’Hare:

Yeah, and Lindsey?

Dr Lindsey Sinclair:

So I came to the plenary from a completely non-lysosome specialist perspective, so I normally work on things like depression and anxiety as manifestations of Alzheimer’s disease or risk factors for the development of Alzheimer’s disease, so nothing to do with lysosomes in my daily work, but what I particularly liked was the way that he was able to make it understandable for someone like me, who didn’t really know an awful lot about autophagy and lysosomes. And I really liked the way, particularly from a clinical perspective, that he was able to relate it to other similar diseases. I thought that was really good, and I particularly liked the inside-out model of where neuritic plaques come from because that made a lot of sense to me. So that was great.

Dr Megan O’Hare:

Yeah, I think obviously, without trying to sell his work, but he was really hammering home that how many diseases the lysosome can cause, defects, or dysfunctional lysosomes can cause, I thought that slide was really powerful where he listed them all. So maybe Lindsey, as you’ve come in from a completely different area, risk factors, what talks and posters stood out for you?

Dr Lindsey Sinclair:

So there were a couple of the sessions which I really, really liked, so the locus coeruleus session which was one of the on-demand sessions, I particularly liked the first talk by Professor Lea Grinberg from the University of California in San Francisco in Sao Paulo. I’ve read some of her work before, but she was again, able to make it really understandable to a non-specialist and was talking about how important the locus coeruleus and the raphae are in the early development of Alzheimer’s disease. And I hadn’t realised until she was talking about it that the volume of the locus coeruleus drops by almost 10 percent with each step increase in Braak stage. So that was a very new piece of information for me, and the other talks in that session were very good but a lot more specialist, so for example, one of them was talking about pupil dilation in mice, another one was talking about human fMRI, so a lot less general and kind of overview-y so it was really good to have Grinberg talking at the top of that session.

Dr Lindsey Sinclair:

And the white matter damage session, which is one of the live ones, had four speakers, so the first one was James Nicoll from Southampton, he was talking about ARIA, which is an imaging abnormality that you see after A-beta immunisation. And from a clinical perspective that was really good talking about where you see these things on MRI but what actually are they? Donna Wilcock from Kentucky was talking about VCID using Meso Scale discovery techniques, and it’s always nice to see new-ish techniques like that being used as larger amounts of data and [proteo 00:16:58] mix, so that was great. And the one in that session that I really, really liked, and would recommend to any clinicians listening was Professor Joanna Wardlaw from the University of Edinburgh, who was talking about white matter hyperintensities.

Dr Lindsey Sinclair:

Now, I’ve been to a lot of talks about white matter in Alzheimer’s disease, I’ve seen loads of scans with white matter hyperintensities but I didn’t know what they actually were, it turns out, until I listened to her talk, I thought it was a brilliant description of what they actually are and why they cause problems. So I’d recommend that to any clinicians listening, or anyone interested in vascular disease.

Dr Megan O’Hare:

Would you like to [inaudible 00:17:42] quickly what they are?

Dr Lindsey Sinclair:

Yeah, sure. So it’s to do with fluid getting stuck in perivascular spaces and that’s what impairs the fluid and water clearance, and that’s why white matter hyperintensities can increase or decrease in size. It’s to do with the amount of fluid and edema, which I had no idea about, I’d thought, like many people, that they were just a permanent lesion. So I had no idea that there was so much of a dynamic component to them.

Dr Megan O’Hare:

Okay, and would that be a potential area of therapy that you could target that area? Or if it’s sort of something somehow you drain the fluid? I don’t know.

Dr Lindsey Sinclair:

So it’s not something that you could go in with a needle and drain, but it will give you a bit more of an idea about when you’re looking at someone’s scans to say is it progressing? Is it resolving? Has it completely disappeared? What kind of evidence of core damage is there that remains? So I think it would make it easier for you to talk to patients about what these white spots on their scans actually mean. And what the change in size over time might mean for them. As well as having obvious research implications.

Dr Lindsey Sinclair:

And then there were a few of the posters that I particularly liked, but I must say, like Louise, I found the whole poster thing quite overwhelming. There were so many of them, and there were hundreds, and you just have to choose from a title and then hope that the pdf loads, which it did for almost all of them. So it took me probably two and a half hours to have a good look through the posters, whereas normally you just cruise past them and go “Oh that looks interesting” or “I like the picture on that.” So it took a lot longer. But the one that I thought-

Dr Megan O’Hare:

Do you think that [inaudible 00:19:42] different ones that may be weren’t so visually impactful but the title really caught your eye, so you looked at them in a different way? I don’t know.

Dr Lindsey Sinclair:

I think probably, probably, because I’m normally a very visual person so it probably forced me to pay more stringent attention to what was in the title, and what might have been in the abstract. So the one which I was most interested in was from Elena Chrysostomou from the University of Maryland, in Washington, who’s developed an online tool called NEMO-AD that uses seven existing data sets to allow you to look at gene expression in particular, genes between different areas, or between different cell types in one area. And I just thought that’s the kind of tool that will be really useful to people when they’re planning studies or trying to work out what to look at. So I thought that was great.

Dr Lindsey Sinclair:

From a clinical perspective, there was a another poster from Alexandra [Vigand 00:20:42] from San Diego, who was pointing out that there’s no consensus on threshold for positivity of tau PET scans which would be kind of helpful to have if we’re going to use them diagnostically. She was saying that some people relate whether a scan is positive for tau to whether it’s positive for amyloid or not. And it would be useful to have a clear idea of how much tau there has to be, in what areas, before you say that it’s abnormal or not. So form a clinical perspective that would be very useful.

Dr Lindsey Sinclair:

And finally, there was a very productive fellow Alzheimer’s Society-funded researcher called Kirsty McAleese from Newcastle who had four posters, all of which were dense with results, and so she’s obviously been working really hard, and again, she just had a very useful practical poster, looking at diagnoses in the brains for dementia research cohort, showing that pure disease is the exception, rather than the rule. So she was talking about how most people have evidence of more than one pathology, which again is just relatively practical and useful and helps you plan studies and not be too much of a purist I think when you’re using human tissue.

Dr Megan O’Hare:

Yeah, she’s done a couple of podcasts for us, she’s very good.

Dr Lindsey Sinclair:

Yeah.

Dr Megan O’Hare:

But four posters, that’s a lot.

Dr Lindsey Sinclair:

Yeah.

Dr Megan O’Hare:

Emily, any posters or other sessions that stood out for you?

Dr Emily Maguire:

So I think that probably, so there was lots of good talks, and I watched a lot of talks and I think the one that I enjoyed the most was one called human brain resilience to AD pathology. And that was by Teresa Gomez-Isla from Harvard Medical School, and I thought it was really cool, because what she was looking at in particular is brains that come from people have tau and amyloid stored in their brains, but they reached the age of 90 and they don’t develop Alzheimer’s disease. So, her idea is to find out what’s different between these brains and Alzheimer’s disease brains where they develop Alzheimer’s, in order to find out what is the root cause of the pathology or what maybe we should be targeting therapeutically.

Dr Emily Maguire:

So these brains, even though they have neuronal tau and amyloid, they don’t show neuronal degeneration in the same way, but one thing that they do have, is they seem to have much less microglial, so the resilient brains have a lot less microglial activation when compared with Alzheimer’s diseased brains. And much less inflammatory cytokine production. And this really ties into genetic studies in Alzheimer’s which highlight microglia as being important in the pathology. So for one, the gene that I work on is expressed in microglia and seems to be important in this as well, so I think this is really important because it suggests that in the future maybe we should be trying to look at therapeutics that are like microglial targeting rather than necessarily amyloid and tau targeting therapeutics. So yeah, I enjoyed that quite a bit.

Dr Megan O’Hare:

Sorry, do you think that those people have effective microglial responses, so it’s that they just have never, their microglia don’t respond in the same way so the normal response would end up with Alzheimer’s disease but this is an abnormal response, or is it that there’s some other, I don’t know, what would be not making them activated?

Dr Emily Maguire:

So I think that they might have resilient brains, they might have genetic or maybe lifestyle factors that means that their microglia respond in different ways to the ones with the plaques and the tangles where they develop Alzheimer’s. If it is, so the changes in the microglia behaviour, so microglia it seems that at a certain stages of Alzheimer’s they can protect against the disease, maybe to slow the progress but they can also, overactivation of microglia can also cause problems in the disease. So it’s probably just changes in microglial behaviour which we’re trying to work on at the moment, lots of people in the field are trying to work on but we don’t know exactly what the specific changes are yet. Does that answer-

Dr Megan O’Hare:

Louise, did you also see that talk?

Professor Louise Serpell:

No, I was just really pleased that Emily decided to talk about it because I saw a bit of it, and I saw a panel discussion where it was mentioned and I thought “Oh this is really fascinating, I want to go back and watch it.” The only thing I did pick up was that, they did obviously talk about activated microglia, but they also talked about there being more oligomeric phospho tau in the synapse, which it’s interesting isn’t it? How we watch things and we pick up the things that feel important to us, so that’s the bit I’ve written down, you obviously talked about microglia, which one is, activated microglia is obviously very important, I did write that down, but it’s the way that I go “Oh P-Tau, I’ll put that down.” So it was really, really good and it’s such a clever idea isn’t it? The whole idea of looking at resilience, what is it that some people have got that somehow stops them from being effected by pathology. So that was the only thing I-

Dr Megan O’Hare:

So in the resilient brains, there was more oligomeric phospho tau?-

Professor Louise Serpell:

No, in the ones in the disease, people who were sharing symptoms.

Dr Megan O’Hare:

Oh in the disease, right, okay. And that was at the synapse specifically?

Professor Louise Serpell:

Yeah.

Dr Megan O’Hare:

Okay, right, so the resilient brains had not got to that stage. Okay. Anything else Emily?

Dr Emily Maguire:

I guess it is true, it’s funny because my main take away from that talk was the activated microglia stuff, but I did think that the phospho tau stuff was also, at the synapses specifically was also really interesting because at the moment I’m thinking a lot about synaptic pruning and synaptic-specific degeneration, and it’s role in Alzheimer’s disease and how that relates to microglia, which are often the ones that prune the synapses. And there was a previous talk in the same session where because it’s quite hard to look at synapses, we’re developing new techniques to do this, and Thomas Montine from Stanford University has developed a new technique called, what is it, called mass synaptometry where he barcodes individually individual synapses from human brains, I think it was human brains, and then he pulls them together and this allows him to examine differences in individual synapses. Which is really cool.

Dr Emily Maguire:

And he found a similar thing to what Teresa Gomez-Isla found, which is an increase in tau specifically at the synapses in Alzheimer’s diseased brains. And he also found increases in injury markers and oxidative stress amoebic [retination 00:28:04] so all kind of damage markers within the Alzheimer’s disease synapses compared to controls, and this technique I think in the future is going to be really good for looking at this and kind of links the two talks together as well nicely.

Dr Megan O’Hare:

I went to quite a few of the microbiome talks which was talking about the gut-brain axis, but also again about immunity and immunology and that sort of thing which I guess sort of links in with the microglia. Did anyone go to any of the microbiome talks? They were probably at the same time as the white matter ones and other ones.

Dr Emily Maguire:

No, but I wanted to, and I’ll listen to them later.

Dr Megan O’Hare:

Yeah, they were good, they were good. There was one, let me find her name, Meiyu Geng from Shanghai, and they were actually looking at a drug or a therapy GV971 that seemed to actually regulate and improve the peripheral immune response, which led to decreased neuroinflammation so it was quite interesting that there was actually a, it wasn’t just talking about basic biology, she actually had a drug therapy that she was talking about. So that was quite interesting. Any other, did you see any posters Emily? I know that Louise and Lindsey have said it was a bit overwhelming just the numbers of them, did you manage to see any?

Dr Emily Maguire:

So I mainly focused on talks.

Dr Megan O’Hare:

Yeah.

Dr Emily Maguire:

But what poster did I like? Well there was one that I particularly liked, and again, it was about the synapse because I guess that was a bit of my focus yesterday. But it’s called early developmental abnormalities in hippocampal synapse distribution in a mouse model of AD. And it was by a guy called [Ajit Ray 00:30:04] and essentially what I thought it was good, again, because more techniques to look at the synapse and it looks like he developed a really cool genetically encoded post-synaptic targeting construct that he used to label the synapses and he got some really, really nice pictures of them and they look really cool, and he was comparing synapse loss in different areas of the Alzheimer’s diseased mouse brain and he found that synapses are lost to different extents and at different stages and in different areas of the brain and I thought this focus was really nice research and also really nice pictures and a really good start for future studies.

Dr Megan O’Hare:

Were there any correlates with where the synapses were being lost? Like we talked about phospho tau or anything?

Dr Emily Maguire:

Well, as far as I remember, he hadn’t looked at that in this study yet, but I would assume that that would be a really nice place, a really nice thing to look at next.

Dr Megan O’Hare:

And what areas of the brain seemed particularly vulnerable to synaptic loss?

Dr Emily Maguire:

So the weird thing is, I don’t know that much about specific areas of the brain, so I could tell you what he put, so in the apical tuft he found that synapses are lost early and then they remain low. But in the distal apical synapses, they’re elevated early and then they normalise at later stages, and then-

Dr Megan O’Hare:

Elevated? First of all?

Dr Emily Maguire:

Yeah, yeah. And in other areas it seems like they’re lost at later stages and sometimes they’re lost at early and late stages. So yeah, basically it’s a complex picture, I think that’s what it shows overall and we should be looking at different brain areas when thinking about it. Although, as I said, my knowledge on, apart from you know, general overview, isn’t great. So I’m probably not the best person to ask about that.

Dr Megan O’Hare:

Anything from you Louise? Did you see any of these other talks that these guys saw?

Professor Louise Serpell:

I can say a little bit about some of them, they all tend to link back to what I tend to look at but I went into some of the on-demand sessions and had a chat with people which was really nice, there was one particular one which was one of the early ones, where I attempted to watch the talks at the same time as talking to people, because I hadn’t been prepared enough. Because you have to get in there really early. And then I talked to Eleanor Drummond who’s in Sydney and she talked about, she was looking at the content of plaque, so she was basically taking plaques and then analysing what was in them to see what the provenance of A-beta was and I guess it tells you about where it’s come from. And the really nice thing about that was that she found lots of endo-lysosomal proteins in there.

Professor Louise Serpell:

So that was really interesting, I really enjoyed that and I also talked to Cora O’Neil who works in Cork. And she works on a protein called [Trip-MAL 00:33:23] which is a calcium channel, which is found in lysosomes, and she’d found impaired function there and she was looking at the possibility of using that as a target for therapy. So that was really nice. And then I went to a different session where they were talking about RNA interactions, quite a lot of RNA interactions with tau. And Lulu Jiang who’s in Boston working with Ben Wolozin had this really nice system, I really like these things where she had made a CRY2 optogenetic tau, which meant that it was being expressed in the cells and then when you shine blue light on them, the CRY2 dimerizes, so you start to get conglomeration of the protein. So you can trigger aggregation and assembly and then see what happens, so that was really nice.

Dr Megan O’Hare:

In very, very specific places as well can’t you do it-

Professor Louise Serpell:

Yeah-

Dr Megan O’Hare:

Yeah.

Professor Louise Serpell:

Yeah, so clever systems to answer difficult questions I think is really, really interesting. And then I also talked to Stephanie Fowler who’s at Colombia and what she’d been doing was isolating vesicles from brain and then characterising what the tau inside them looked like. And what she’d found was that the region of tau that they’d found was repeat three and repeat four, which was really interesting because it correlates with the core of tau which has been found from cry UAM studies of [pertilicle 00:34:58] filaments so she was essentially looking at tau that then goes on to form these pertilicle filaments.

Professor Louise Serpell:

And some of these interactions are really fascinating because then I emailed a few of those people, had a chat with them, maybe gave some, we had a bit of exchange of ideas, so I think what I would really encourage people to do is to go into those chat rooms, so the first one was a Zoom one, so we could see everybody, and that was fascinating but then the second one was just typing. And Stephanie Fowler actually, I typed in after the whole thing had finished and she eventually replied to me, and I just think that this sort of interaction is, it’s not the same as seeing people in real life but possibly it’s more inclusive.

Professor Louise Serpell:

Because I what I really encourage people to do is just to talk to Ralph Nixon, talk to people that you possibly might be worried about just walking up to at a massive AAIC conference, but you can ask questions and have a conversation with people and I’ve said, I don’t think anyone knows who I am so it’s just having a really nice interesting chat about things. I found people to be very open and interested in your point of view.

Dr Megan O’Hare:

Yeah I’d not actually thought about networking virtually [crosstalk 00:36:24] I just hide at home in my pyjamas, but yeah you’re right, I probably wouldn’t go up to Ralph Nixon in real life but you could send him a question or whatever, he can always ignore you.

Professor Louise Serpell:

Exactly.

Dr Megan O’Hare:

[crosstalk 00:36:38] to ignore someone in real life or, well if they do it’s soul-destroying.

Professor Louise Serpell:

But for example, Ben Wolozin, I’ve been reading loads of his papers and he works on stress granules and what’s in stress granules and whether they are the precursor to aggregation, particularly focusing on tau at the moment, but also in some of the other diseases like [pherson 00:36:58] TDP43 and things like that. And it was really nice just to type conversation with him and he just came across as really nice and really open to people’s ideas so. Yeah, so that’s my recommendation anyway.

Dr Megan O’Hare:

Well let us know if you [inaudible 00:37:18] from this.

Professor Louise Serpell:

You know, I think that that’s one of the, what I miss about going to conferences, is that sort of conversation that you have with people over the coffee table or something like that, and it’s really nice to find that a virtual meeting can provide that, although not quite as well, but yeah, possibly with some positive sides to it that we wouldn’t get in real life.

Dr Megan O’Hare:

Yeah, I guess people have had three, four months practice now doing things virtually haven’t they? So it’s not quite so awkward, we’re used to communicating with our families like that so maybe it’s benefited from being in July and not right at the beginning of lockdown when people wouldn’t have quite known how it worked. But yeah, we were talking this morning about obviously, for the environment it’s much better to have it virtually, but you’re missing out on certain things. So whether you could do every other year you have a face-to-face meeting, otherwise it’s virtually, I don’t know, but it seems to be working well, we should all try networking like Louise did. That’s the next stage. So are there any other final points you’d like to talk about? Lindsey, we haven’t really talked about any risk factors that you found or anything like that.

Dr Lindsey Sinclair:

I don’t think there was so much focus on risk factors or at least not in the sessions that I watched yesterday. The only one, the only other one even, which I would mention just from a clinical perspective, was a small-ish clinical trial done by a chap called Jurgen Claassen from Nijmegen, who was looking at cerebral autoregulation in Alzheimer’s disease. And there have been fairly classic studies apparently showing that cerebral autoregulation is impaired in an APP mouse model, and certainly clinically there have always been discussions about do we put people on antihypertensives, because they may have an element of vascular dementia, or do we worry about reducing cerebral blood flow. And he showed looking at calcium channel blockers that you can drop peoples blood pressure and it doesn’t affect their cerebral blood flow.

Dr Lindsey Sinclair:

So from a clinical, again, quite practical perspective, it’s useful to have research like that, saying that you can treat people and without worrying about completely knocking off all of their perfusion. I would echo Louise’s comments about networking, I’m always far too scared to go up to important people in the flesh, particularly if they’re surrounded by friends or other people asking questions, so I think that if you’re shy then just typing something and hoping that you might get a reply is great. And I think the AAIC actually said at the start of the plenary that they’re planning on doing more virtual sessions in the future, which is obviously more inclusive for people from other countries which may be less funded in terms of travel grants and it just makes it more accessible to a greater number of people.

Dr Megan O’Hare:

Yeah, and as you said at the beginning, childcare or going away to America for two weeks possibly isn’t possible for a lot of people-

Dr Lindsey Sinclair:

Yes. I can’t think of many conferences where they’d let you sit feeding a baby in the middle of a session.

Dr Megan O’Hare:

I don’t know, they have the cinemas don’t they where you can take your baby and feed your baby so.

Dr Lindsey Sinclair:

They’re normally quite loud.

Dr Megan O’Hare:

And Louise has just pointed out to me that Friday is the ask the expert day, so that will be the day where we can all send our questions in. Build up our confidence throughout the week, and then get ready to do it on Friday. So thank you and I assume you’re all going to attend some talks today.

Professor Louise Serpell:

And fit some in but I’m hoping that it might be possible to watch them later.

Dr Megan O’Hare:

Okay, yeah, yes that is also the beauty of all the on-demand stuff, that the live sessions will then be available, I think Emily you said in 24 hours after the broadcast so we can pick those up again so yeah, thank you guys. I’ve enjoyed our chat.

Professor Louise Serpell:

Lovely to talk to you, thank you Megan, and really nice to meet you both Lindsey and Emily.

Dr Emily Maguire:

Yeah, it’s been great, I think today I’m going to catch up on some of the sessions that you guys mentioned, I don’t know much about white matter damage in AD, so I’ll give that a go. And what’s the RNA one? Tau RNA, that sounds good.

Dr Megan O’Hare:

And you’re going to write someone a question, yeah? Virtually network.

Dr Emily Maguire:

Networking. [crosstalk 00:41:58] working side a lot.

Professor Louise Serpell:

I wanted to say something about that, because I’ve been one of those people who sits on a table who’s the ask the expert, and then the idea is that someone comes and talks to you at lunchtime, and it’s the worst thing in the world when you’re sitting there by yourself and no one comes to talk to you. So what I would say is, the people who are running those sessions want you to ask questions, they want it to be all buzzy and interesting and so yeah, that’s what I think, people want to hear from people, they don’t want to sit there all by themselves feeling a bit sad.

Dr Megan O’Hare:

Yeah, also as soon as you ask a question it prompts someone else to ask a better one so you know. But thank you guys, enjoy the rest of the week and everyone else, we are recording another podcast, we’re recording one each day this week except Friday I think, so anyway, catch our next one. Bye.

Voice Over:

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