Transcript
WEBVTT
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This is a podcast about One Health the idea that the health of humans, animals, plants and the environment that we all share are intrinsically linked.
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Coming to you from the University of Texas Medical Branch and the Galveston National Laboratory, this is Infectious Science, where enthusiasm for science is contagious.
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So today we have a special guest here in our podcast, dr Mauro Montalbano.
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I'm trying to say that with my best Italian accent, which is non-existent.
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He's an assistant professor here at UTMB and then at the neuroscience department, and we'll hear some really exciting work that they are doing in that department, and he will also tell us a little bit about the connection to some of the amyloid buildup in the brain in form of dementia, and so we're very excited to have him here.
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So what are we going to ask him?
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Yeah, so tell us a little bit about your lab's current work.
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Okay, so first of all, thank you for having me here.
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It's a pleasure.
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I actually hear some of your podcast.
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That's super cool to be here.
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Great, we have listeners.
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We have listeners on the show your.
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Italian is perfect.
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So that is 10 out of 10 for my last name.
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Yeah, so a brief description of who I am.
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So I'm assistant professor at the Mitchell Center for Neurodegenerative Disease at UTMB.
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So my lab work mainly to study how protein aggregates within the human brain, in particular in Alzheimer's disease, but we cover other neurodegenerative diseases like Parkinson's disease, frontal temporal dementia and amyotrophic lateral sclerosis as well.
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So our vision is to find a way to basically slow down or completely block the buildup of this protein aggregation within the human brain in aging process.
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Basically, Perfect.
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So, now that you've given us a little bit of background on your work and your lab, can you give us a little bit of background on yourself?
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So about me?
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Okay, he's the best soccer player that we have on YouTube.
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Yeah, rather than that, I'm a little bit out of shape, but anyway.
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Yeah, basically, I'm Italian, so I come from Palermo, sicily.
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Is this really Italian, though, like Sicily, is always like its own little Italy isn't it?
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Yeah, exactly, we consider ourselves before Sicilian and then Italian.
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It's like Texans before Americans, oh really.
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Oh, wow, that's cool.
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Yeah, it's beautiful, so don't ask me why I end up in Galveston.
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It's a downgrade yeah exactly.
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But yeah, basically my background is I got my bachelor in biological science, then my master in molecular and cellular biology at University of Palermo and then for basically an international program between University of Palermo and UTMB.
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I ended up as a PhD student and I work in surgery department studying hepatocellular carcinoma.
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So my background was mostly cancer biology.
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But then after that I discovered the neuroscience during my postdoc First postdoc, actually, always here under the mentorship of Dr Modamedi, studying the amyloid formation in the retina of patients with Alzheimer's disease Interesting.
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And then I joined Dr Cayet's lab in the Mitchell Center to study in deep the formation and the buildup of these protein aggregates.
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Side effect of that is that we are not only studying the protein aggregation but in particular we are focused also in gene expression.
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So we are giving another point of view of the typical vision of protein aggregates in neurodegenerative diseases.
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And when you talk about protein aggregates, are we always referring to those as like prions, and are they a natural part of the aging process for humans?
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So this is a really good question.
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I would like to answer that, say that it's under investigation.
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Still, we know exactly which are the two major factors that during the pathogenesis of Alzheimer's in particular, two proteins are involved on that and they are considered quite officially pre-like protein Then I will spend a little bit more time on the terminology and they are the amyloid beta and tau.
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These are the two major factors, so they act as a prion.
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This is well studied, well recognized, but there is still a strong debate in the field to consider it completely fully prion protein.
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So we know, for example, that if you have neurons, for example, in culture in the lab, you expose them to this prion-like protein, the endogenous protein.
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So the endogenous amyloids, endogenous tau.
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They start to misfold and then aggregate.
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It's like exactly the prion protein, exactly the same principle, but still the field is preferred to put a dislike on the side, because the question is okay, but if you, for example, get in contact with those, you will develop the disease.
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This is not what happened actually, or there are no evidence on this, like for the prion disease itself, right, but the principle of spreading or the formation of the first aggregates is exactly the same principle.
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So you have a beautiful protein.
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They do their function for some reason that we still don't know.
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A certain point during our aging process they misfold, they acquire the not proper structure and they spread up this kind of toxic structure to other protein.
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Let's say, for example, for tau.
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Tau is a very nice protein.
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It usually binds a tiny structure within our cells called microtubules.
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These are tubules that keep up with the cells and maintain their shape.
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So if this tau protein misfolds, basically the cells start to have some problem and this tau, misfolded tau transmits to the other tau protein the misfolded shape.
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They start to basically do not function properly.
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They start to aggregate, they start to accumulate and later on these determine the death of the cells, in this case of the neuron, and that's the neuron are not replicative cells.
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So when we lost a neuron we lost forever.
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But think about the crazy things is that this happened in a very big time lapse for the humans.
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People can with the disease for 20 years, 15, 20, 20 years.
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So it's a very slow process.
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This is why many labs now focus on the early onset of the disease, when the tau or the amyloid start to form what we call prionic oligomers.
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So cool.
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I have so many questions.
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I think every five questions just popped into my mind.
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Yeah, I'm just kind of some rapid fire for me.
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So do you know if animals have alzheimer's disease, or do you have something comparable in the animal kingdom?
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so I will answer you with a maybe no means.
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I'll'll explain.
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I'll explain so pathological-wise.
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No animals really develop what human develops in terms of pathology.
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There is some study that show up that something that is comparable to the human pathology happen in some species of monkey, and I guess they're called marmoset, as I recall.
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They're a small monkey, but other animals do not develop what humans develop.
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This could be to the fact that humans age much longer than others.
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And other animals age naturally, but our aging process is very how I can say it's been improved strongly.
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If you think, 100 years ago the average of our age wasn't the one that we have today.
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So in a century or in two centuries we basically doubled the expense of our life.
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So this presented a new challenge for the neuronal biology or the brain biology itself.
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This is valid also for other organs.
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So my cat just turned 19 and I think she has Alzheimer's disease.
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Sometimes she forgets where stuff is, so maybe I have this possibility to challenge the dogma right.
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How many cats live till 19, though she's got a vet for a dad.
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That's why she's like that's fair, Although I bet if you put her in an MRI you might see other stuff that you.
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Going back to your question, for example, we use mice as a model.
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Mice do not develop naturally right alzheimer's, so we have to create a transgenic mice that basically reproduce what we found out.
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And this is the reason also why, unfortunately, many clinical trials do not work out in human.
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Because they work perfectly mice, we clean the mice brain perfectly.
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There is a colleague that to make fun about it, to say we can cure Alzheimer's in mice.
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So this tells you how much is complex Study this kind of disease in animal models like mice, for example.
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Yeah, but the lifespan of a mouse is only two years, right.
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But they have so many other properties that make their brain very resilient to the prion spreading and aggregation itself, because they possess, for example, a very reactive inflammatory response compared to the human.
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We think right now, in the last years, that now inflammation in the brain play a crucial role for the buildup and the early manifestation of this protein aggregate.
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So that's what I was going to ask what is driving that sort of original kind of misfolding?
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Is it a traumatic brain injury?
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Is it inflammation?
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Is it like potentially toxicity from?
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something.
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If I have the answer for this question, I'm not maybe here, I'm in Sweden receiving the Nobel Prize.
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So that's a great question, no, look, I report every time an example I had in my family side of my grandma and auntie basically, and she died with Alzheimer's disease.
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And this auntie lives in a family of nine.
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There are seven brothers, my auntie and my grandma.
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So she developed Alzheimer's on her 60 around.
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I love her, it was like a second grandma for me and she developed the Alzheimer's.
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And my grandma two days ago did 99 years old she just made her birthday and they were sisters.
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So the reason lies down probably to many factors.
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These diseases are multifactorial diseases.
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For the last 20 years people focus just on amyloids.
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Right, it's the amyloids, the plaques.
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We have to block this stuff and we will cure the disease.
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We have to block this stuff and we will cure the disease.
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After 20 years the FDA approved just two antibodies for amyloid and the process is very slow.
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But the example of my grandma is just to tell you that they live in the same family, they have the same kind of education, they have basically also a comparable genetic background.
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They were both sisters and one developed Alzheimer's and one make 99 years.
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And I would assume they both lived a fairly similar lifestyle as well.
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Exactly Similar lifestyle, similar diet similar physical activity.
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No, physical activity because at the time there were no gym or they should take care just of the family.
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Very low also education One of the risk factors for Alzheimer's, for example, has been established that low education, for example.
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So if you keep your brain low with low activity, so you read or you do exercise or all those brain games that are cool things that keep up with and counteract actually the build-up of this protein.
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But the truth is that is a multifactorial thing.
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Multifactorial thing and this bring complexity we we would like to make in the past easier.
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Because you find out prion aggregation.
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They usually in the brain forms at the beginning in a very specific brain region that is called the hippocampus and entorhinal cortex.
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This is the region that generally people associate with the memory.
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In fact memory is one of the cognitive dysfunction that usually people develop in Alzheimer's.
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But then what happens is like a prion, once the neurons die, or through the inflammatory system.
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Once the neurons die or through the inflammatory system, so they are called in the brain microglia and astrocytic cells, astrocytes.
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So basically it looks like these cells are not able anymore to manage the cleanup that usually occur in our brain during aging and they also mediate the spreading across all the other regions of our brain, the spreading across all the other regions of our brain, and gradually they bring dysfunction in many cognitive aspects of our life.
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So the astrocytes and the microglia assist in the spreading of these misfolded proteins.
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Initially they assist to clean up, but at a certain point, when the system is overwhelmed, there are theories that actually make it faster or there is a strong debate still on that.
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It's very fascinating.
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But the job basically is to clean up the microglia.
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For example, take care of our synapses and the synapses are those portions that connect one neuron to another neuron and make us functioning for all our cognitive or physical activity.
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And actually when these amyloids forms at the beginning of the disease, the synapses that looks like are the most sensitive parts of our neuron and they burn and microglia usually come close to those synapses that are damaged and they start to eat.
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Clean up all those surroundings, try to keep the neuron as much as possible functional.
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But when you have an overwhelming amyloid formation when I say amyloid I include also the tau protein, the other component they start to get, let's say they're not able to manage it anymore and they acquire some of them.
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There is like a beautiful papers published on it.
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Some of these microglia start to became what they call disease associated microglia, so make the prion spreading even faster.
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Interesting, in fact, in people that have a very fast, I'd say, first development of the disease, they have a very strong microglial activity Interesting, so it's very interesting.
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But also the aspects that we have to consider are so many that we need to go step by step on each factor.
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So just to recap, so you were saying with the microglia, so they normally come in, they clean up, right, and what I know about prion diseases is that they accumulate within the cell and then the cell cannot get rid of them.
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So what are you saying is the microglia come in, they pick up the disease or the particles of the cell that was diseased, and then they move to a different place and they carry the amyloids with them to a different place.
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Is that what you're?
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saying yeah, that is one of the mechanisms.
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The other mechanism is that this transmission happens neuron by neuron, for example through the synapses themselves or through the secretion of exosomes or other microvesicles.
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Think about that.
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This process, as I say, happens long in time.
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Okay, it takes a while.
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So our neurons do not die immediately, so they have a certain capacity to rearrange.
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Another theory is that, anyway, we form some sort of aggregates, even in normal aging.
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There are cases of people that have the pathology, for example, but they do not show any cognitive symptoms or cognitive impairments.
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So there is a system, for sure, that is able to manage even the presence of the prion and amyloids, the plaques, the tangles of tau and whatever.
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But maybe these people have a stronger process that is able to manage it and the cognitive function are still integrated.
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But, as to recall, this is always on the synapses.
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But the synapses are very sensitive cellular portion to the prions because they've been binded and then this should work as a signal for the microglia.
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So, okay, this synapses is not properly working, I'll engulf, I heat it and then I will degradate.
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But again, which is the microenvironment around, how the other, also the astrocytes, are working up on this.
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So this is still under investigation and I guess many new tools and also for the therapy actually is focusing on keeping an inflammatory state very low.
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So that is another possible therapeutic intervention.
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I was going to ask do you know the role that, like circulation and like good or improved circulation, potentially plays in the development and the progression of Alzheimer's?
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Because I know with other neurodegenerative diseases vascularization throughout the body plays a really big role, like in maintaining the integrity of neurons and the myelin sheaths and stuff like that.
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So is there like a well-known role that vascularization plays in Alzheimer's?
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Yeah, this is a great question.
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So there are a study and it's well-established also that exists a form of vascular amyloidosis it's called, where basically the amyloids not only form in neurons but form also and form plaques within the blood vessels.
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Now where this comes from the neurons, or is it just the endothelial cells, for example?
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I don't know, but it's recognized.
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It's called CAA cerebral vascular amyloidosis and this is quite a form that you can find in Alzheimer's as well in Alzheimer's patients, but not all Alzheimer's patients develop the deposition of amyloids, because there is also the possibility that your brain is overwhelmed with these amyloids.
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The spreading is on, and another way that maybe our body has to clean up is to flush out these amyloids through the vessel.
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But again, how much amyloid we are talking about is not just amyloid, beta, it's tau, Maybe it's even other proteins.
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I like Christina's question, I want to ask basically from a different angle.
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So we live in a society where so many of us suffer of bad vascular health, right, atherosclerosis, hypertension, hypertension and stuff like that and atherosclerosis for listeners is essentially your blood vessels are getting clogged, and it is very common in America and all over the world.
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Absolutely yes, and thank you for clarifying that.
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So is there a correlation between bad blood flow to the brain, or atherosclerosis, and Alzheimer's disease?
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It's definitely a risk factor.
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It's definitely a risk factor, but even the sleeping has been found has an impact on the development of alzheimer's or form of dementia.
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So little sleep is risk factor yeah, I don't know what that means with bad sleeping, but like an interrupted sleep or I'm not an expert on sleeping, but I know that sleeping is playing a crucial role.
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I'm an expert on sleeping.
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Another association has been done with auditory system, and if you have issues also with your ear, really yeah, because that does not stimulate certain parts of your brain and make your neuron maybe even vulnerable.
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I don't know exactly the mechanism, but many aspects of our lifestyle impact the working process of the brain.
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So basically the principle right now, because there is no cure for this disease, so, like for other diseases, have a good lifestyle, eating well.
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But this is valid in general for any kind of disease, for cancer, for cardiovascular diseases and even for dementia.
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But again, we discussed before the low study or like low education didn't work out for my grandma.
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She reached 99 years old without any form of dementia.
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But again we still need to dig more on the cause.
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Maybe we are just seeing the effects.
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Like the amyloid and the prion themselves is a strong event.
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That happened at the beginning.
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But we still don't know exactly what they are inducing as well.
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Human brain is so complex, very hard to study, so it's very challenging for me as a scientist in the field exciting to study.
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So, mauro, I want to come back to your point of the sleep quality that you refer to, that sleep has an influence on this.
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So there's a new class of sleeping aids that have been released now.
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Right, we used to have the GABA receptor-based ones, and there's now this new class that basically reduces your wakefulness, and I saw there was an article that speculated on that.
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It actually can help reduce Alzheimer's, and I don't know what the mechanism is or how it would avoid accumulation of amyloid.
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Do you think that's a crazy idea?
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Have you seen those reports that this could?
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be a treatment.
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I didn't see those reports, but maybe it will detect some impact somehow.
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But I don't know.
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Honestly, it's hard to say that.
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Maybe the other problem is to see an effect on the incidence of some therapy or something.
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Anyway, you need a larger time window.
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Maybe this study will, or the treatment of a particular compound or something that we regularly use.
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The correlation will be found in 10, 20 years since it's been developed found in 10, 20 years since has been developed.
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So my question with this is I think that there's always this strong interest in curing in a lot of like pharmacology stuff, but what you described earlier is that people can have the pathology of this in the brain but not have symptoms, and so we coexist with this, or some people can coexist with this right, Just like we might have staph on our skin, but it's not a problem, unless we have a severely deep cut and then it's in our general system.
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Potentially, plaques aren't the problem if they're not becoming widespread and your body can keep up on managing them, right?
00:23:22.768 --> 00:23:28.766
So is the interest then in preventing, like in the field of Alzheimer's research?
00:23:28.766 --> 00:23:37.925
Is the interest in preventing the plaques from forming at all or in finding a way to help the body continue to manage the plaques that might be forming just naturally?
00:23:38.287 --> 00:23:39.249
Yeah, that's great.
00:23:39.249 --> 00:23:42.936
So the approach at the beginning, many years ago.
00:23:42.936 --> 00:24:01.907
This is why we, the FDA, approved two antibodies right now available for the amyloid plaques, because many years ago, with the study of the plaques, scientists say, okay, this is a difference between an Alzheimer case and a person that do not have.
00:24:01.907 --> 00:24:07.705
So if we maybe we block or we degraded these plaques, we can cure the disease.
00:24:07.705 --> 00:24:10.210
But again, was not this the case?
00:24:10.210 --> 00:24:16.980
Okay, so imagine also that when people develop plaques or this is the very final stage.
00:24:17.526 --> 00:24:23.659
So to me as a scientist on the field, it's hard to think about a cure for late stage.
00:24:23.659 --> 00:24:29.038
It's almost impossible because at this stage, basically, the patient already lost.
00:24:29.038 --> 00:24:32.934
It's not just the loss of neurons, but it's the loss of the connections.
00:24:32.934 --> 00:24:34.646
Remember our memories.
00:24:34.646 --> 00:24:42.588
Our task has been made by an intricate system that we still don't know exactly how to work it out.
00:24:42.588 --> 00:24:50.567
So when you burn out or you lost that neurons, you could lose forever those memories.
00:24:50.788 --> 00:24:56.038
So thinking about a cure in late stage, I don't think even is convenient.
00:24:56.038 --> 00:25:11.398
So this is why our labs in the Mitchell Center, for example, we are more focused on the early phase, where those prions start to form and they are still small and toxic, yes, but maybe targetable in terms of therapy.
00:25:11.398 --> 00:25:13.972
And the other is the prevention.
00:25:13.972 --> 00:25:23.395
So there are many groups that are working to identify people that are vulnerable to the buildup of these protein aggregates.
00:25:23.395 --> 00:25:24.317
That would be cool.
00:25:24.317 --> 00:25:34.638
Maybe we can produce in the near future a vaccine, a kind of a vaccine that can prevent, for those that are more at risk, to develop dementia.
00:25:34.638 --> 00:25:47.759
So that is where the field is going using immunotherapy, so antibody, or, as in our case, starting to use genetic therapy, so a genetic approach Interesting.
00:25:48.926 --> 00:25:58.920
Could you also clarify the difference between Alzheimer's and dementia, because I feel like in the public space, people often use them in a way that's interchangeable, but they're not right?
00:25:59.025 --> 00:25:59.970
Yeah, no, they're not.
00:25:59.970 --> 00:26:11.718
But with dementia we identify all those kinds of brain pathologies that basically impair the brain functionality at different age.
00:26:11.718 --> 00:26:19.089
Okay, because, again, alzheimer's, usually the first symptoms start around 65 and can last for longer.
00:26:19.089 --> 00:26:26.017
But there are other forms of dementia, like frontotemporal dementia, that can develop even before in age.
00:26:26.017 --> 00:26:29.976
Okay, so, and that is due to a buildup of other protein.
00:26:29.976 --> 00:26:36.673
In this case one of the most important is TDP43, is another amyloid protein.
00:26:36.673 --> 00:26:44.175
So maybe we have to deal even with more loidogenic, so prion-like protein, so that the picture is more complex.
00:26:44.704 --> 00:27:03.476
The Alzheimer's disease in the last years we are starting to differentiate also maybe the Alzheimer's disease because there is an historically, naturally I would like to say chain, because this is associated with who discovered the disease, observed for the first time, even within that, what we call Alzheimer's disease.
00:27:03.476 --> 00:27:06.410
We have to differentiate this form.
00:27:06.410 --> 00:27:11.380
But yeah, with form of dementia, we always put Alzheimer's and many others forms of dementia and remember these are always progressive.
