Repetitive injury, herpes, and Alzheimer's

From Microbe TV, this is Twin, this week in neuroscience, episode number 57 recorded on January 27th, 2025. I'm Vincent Dracanillo and you're listening to the podcast about the nervous system. Joining me today from New York, Tim Chung. Hello. Hi, Vincent. Just a two of us today. It is. But we will, we will keep it, keep it lively. Yeah, no problem. I have no problem. As long as I have at least one other person, we can do it. If you like these programs, science programs, these are about real science, you know, not fake science, not this information. We'd love your support so we can keep doing them. Microbe.tv/contribute. So over on TWIV, in fact, the latest TWIV is called the Tao of Herpes virus. I saw that. And it's an interesting study where infection of brain, I forgot what systems they used. It may have been mice, organoids or something. Yeah, they did organoids. Faction causes phosphorylation of Tao, which is a, I think, a thing that leads to neurofibral airy tangles, right? Yeah. It's a major, major contributor of a big family of new degenerative diseases called Taoopathy. Yeah. Yeah. So the interesting thing from that paper was that when herpes virus, in fact, Tao is phosphorylated as part of an innate defense. And it protects neurons. It protects them from dying. But having phosphorylated Tao is not good, because it leads to neurodegenerative disease. And so in that paper, they show, in fact, that Tao is phosphorylation and herpes virus infected brains is a problem. So that's interesting. And this paper, then I saw this paper and it's got it. It's got my interest too. This is in science signaling. Repetitive injury induces phenotypes associated with Alzheimer's disease by reactivating HSV1 in a human brain tissue model. No authors are cairns, smiley, smiley, corsandian, kelly, it's sake and Kaplan there from Taoopathy University of Oxford and the University of Manchester. So traumatic brain injury, TBI, we've got some acronyms. You're going to have to remember, unfortunately, is a risk factor for neurodegenerative diseases. And that includes Alzheimer's and chronic traumatic in cephalopathy, you know, football players and boxers, they get that from having their head smashed constantly for years. Yeah. Not good. But we don't know how injuring the brain leads to dementia. And that's what this paper is all about. And so there are two kinds of head injury. There's penetrating and non-penetrating. So penetrating, this skull is broken and the underlying brain tissue is impacted. So that's really severe injury. And non-penetrating or closed head injury, CHI, jostles the brain without breaking the skull. Yeah. That's what happens in a concussion, which is much more common in I think most of us and also definitely sports players. Yeah. So my mild non-penetrating TBI concussion is a loss of consciousness lasting more than 30 minutes, alteration of consciousness or post-traumatic amnesia lasting less than 24 hours. Yeah, it actually happened to me last year. I don't know whether you guys noticed by my performance on twin. I actually got sight swiped by a car when biking home. Wow. And the car hit me and it split my helmet completely open. Wow. And I work up in the hospital with a concussion where the doctor asked me, do you know what month this is? And I had asking no idea. I had to like reason. I had to talk to say that tells me I told the doctor, well, it's a few kind of cold, but I'm wearing pants. I'm wearing shorts. So I'm guessing it's autumn, is it October? And she said, no, that's not good enough. So yeah, she wrote me to have a concussion. And I have no memory of the incidents and it took like maybe a few hours before my normal brain function came back. Yeah. It's quite a, but definitely wear helmets if people are listening and are biking. Well, years was split in half, right? The helmet was split in half. So without the helmet, it would have been, who knows what would have happened. It would have been much more severe. But yeah, it's, it's not good. Concussion is not good. But it happens to wait too often. So well, you've only had one, right? That's good. I only have one so far. As we'll find out, it's these things can, can get worse if you have more of them. Anyway, if you get repeated ones of your playing sports, right? Yeah, absolutely. You can get progressive neurodegenerative disease or chronic traumatic encephalopathy. Now, mild TBI affects millions of people each year, including Tim. And hard to know the extent of injury. But a single in studies, a single prior head injury was associated with an increased risk of dementia. And two or more head injuries further increased it. And over nearly 10% of all dementia cases in the study population could be attributed to at least one prior head injury. It's also been found that the lifetime probability of dementia after TBI is around one point times the background risk, which is higher after more severe injuries or greater number of injuries. So there's a dose effect. So what, what pathway is leading from TBI to dementia? We don't know. This is what this paper tries to address. There are characteristic events during delayed secondary CNS damage that are known. You get beta amyloid plaques and neurofibriillary tangles. I thought something that might be worth interesting to point out is these dementia and Alzheimer associated symptoms from chronic repetitive concussion and TBI traumatic brain injury. It seems to be happening. It takes a long time for it to show up. It's known you have a few concussion and suddenly you have concussion and you do do much worse. But then these kind of dementia, your mental function gets better after some time, after concussion. But then there's a secondary risk factor that comes on where you become dementia. So that's the mechanism that is hard to figure out because acute brain damage probably explains a bunch of stuff. But there's slow kind of innovation. So they were trying to understand. So individuals with the APOE4LEAR allele are at higher risk for TBI's. Yeah. And it's also APOE4 is also a risk factor for Alzheimer's in general. Yeah. So when they make Alzheimer's mouse models, they typically put APOE4 in, right? Those are several ways of several Alzheimer's model. APOE4 is one of them. And I think like it Amelot precursor protein, which is the protein, we'll talk about it, but that's the protein that actually makes these Amelot plaques, abysa plaques. That is also another mutation that people put in mice to model. So in this paper, they look at herpes virus, right? Infects a lot of people over 80% of people by the age of 60. It's highly prevalent in human brains. And in APOE4 carriers, it confers strong risk of Alzheimer's disease. And in three-dimensional modeling of the human brain, with an APOE34 genotype, lately infected with HSV1, the addition of other infectious agents causes reactivation of the virus, the endduction of neuro-information. So you've probably heard people with COVID get reactivation of HSV1. That's the mechanism by neuro-inflammation. The idea here is that HSV, so it's typically in the peripheral nervous system, it travels to the brain in older people as the immune system declines and remains there in a latent state. But subject to repeated episodes of activation caused by events like stress and infectious diseases. And this is a revelation for me that in many people, elderly people, you have latent terpy simplex virus in the brain. It's not good. And currently, if I'm wrong, but I think herpes simplex virus like one. So HSV1 is the virus that causes coltsaw as it kind of, if it comes, if you're under stress, your coltsaw flares up and that's because of the herpes, HSV kind of showing up. And APOE4 is a risk factor for gold source, too. Interesting. So presumably, it's due to interaction with the immune system, perhaps? We don't know. It's a good question. In humans, infections like SARS-CoV-2 can reactivate latent HSV1 and other herpes viruses, especially where our cell is oster, which causes chickenpox and shingles, probably explaining the postulated involvement of agents such as VZV and Alzheimer's disease. So chickenpox, actually, if I remember correctly, I think in one of your previous episodes of twerf, you guys talked about pre-liminary study. Maybe it's a pre-print where they looked at shingricks, chickenpox vaccine, kind of reducing the risk for dementia, not quite Alzheimer's, but dementia. So there's some link going on as well. So what they're thinking here, a blow to the head might reactivate HSV1, right? So if it's latent in the brain, it's DNA is in the neuron, and it's quite it, a blow to the head might reactivate it by inflammation, right? When you have a blow to the head, boom, you get inflammation. And this has been observed clinically. So that's what they looked at here. They look at the effect of TBI and reactivation of HSV1 and the induction of AD-associated phenotypes. They have a 3D human brain tissue model, which mimics various types of brain injury and vitro, and their findings support the idea that reactivation of Ques and HSV1 DNA by repetitive injury exacerbates the AD-associated phenotype. Yeah, I cut a quick look at the 3D human brain model, because I had no idea what that is, because I work with mice. And essentially, apparently, it's like a doughnut-shaped scaffold of silk things. And then you can just grow, you soak it in human, in juice, pull the protein stem cells, and cause them to differentiate into neurons in this doughnut. And there you have kind of like a 3D structure that kind of, not quite resemble a brain, but as a model of perhaps brain tissue. Yeah. So they subject these to injury, cortical impact, or CHI, and allow them to recover. So CHI being close-head injury, which is that injury? Yeah, so I look like the cortical impact injury is you have this 3D brain doughnut thing, and you slam like a pile driver onto it, like you just slam like a metal rod into it. So it's quite severe brain injury, kind of they model it as the kind of the penetrating, perhaps penetrating brain injury where your skull's broken, and it's very bad. And the close-head injury, it looks like they encase the 3D brain model in a cup with like calcium medium to kind of encapsulate it. So it's kind of like a brain flowing, sitting in a cerebral spinal fluid, and then they put it in a box, and then they kind of shake the box up. The box is on a spring, and they just make the box who are back and forth, a bunch, and that mimics the slightly milder close-head injury, that similar to a concussion, it seems like. So these injured tissues have negligible beta amyloid production, but a lot of gliosus, right? Increases of glio-fibralaryacidic protein that are usually made by astrocytes, people think it is. Astrocytes kind of reacting to like an injury, potentially forming things like gliosgar that we talked about before. So yeah, so it tells you that the head injury model that they did actually did cause the 3D brain model, 3D brain to react to the injury. And these CCI, the aggressive injury, almost complete loss of cells in these cultures. So they say this is probably a better model for mimicking mild and repetitive injury in vitro. So the CCI is probably better for mild, because it didn't lead to cell loss, the closed-head injury one, the CCI, the one with the traumatic pile driving into the brain, that one is probably too severe, actually. Yeah. So then they infected these brain models with HSV1, either Mach infection or low level, MOI 0.0001 for 10 days. Is that normal? Vincent, is that like a really low number? That's hugely low, yeah. Oh, okay, okay. I think they don't want to do any cell damage, probably. It might actually reflect, because in people with latent HSV infection in the brain, it probably is not every single cell that's infected. Right. Yeah. So they stain these tissues to look at HSV1 and beta amyloid and also GFAP, and they see robust gliosis, and also the presence of phosphorylated tau in these cultures. So yeah, so I probably should quickly jump in and explain a bit about one of the beta amyloid, which is one of the proteins that researchers look at as an indicator, as a measure for Alzheimer's disease, associated symptoms. So in patients with Alzheimer's disease, in the brain, you see a lot of these plaques, they call abeta plaques, and these plaques are extracellular deposit of this protein called amyloid beta, or beta amyloid. And these beta amyloids have become insoluble, so pathologically insoluble, and they tend to clump together to form these plaques, in a way that people think might mimic a bit like preons, so they kind of spread, and they kind of attract more misfolded, misform abeta plaques to kind of come onto it, and they might be toxic, there's huge debate about whether they are toxic or not. But people have found that in patients with Alzheimer's, there are these plaques. So the researchers have used the presence of these plaques, abeta, well at least these abeta proteins as a way of, as a proxy measure of the Alzheimer's disease phenotype, and something that's quite interesting is, I don't know where they remember Vincent, but in a previous twiff, so I made, I took notes on it, it's twiff 519, let's see, what is it called? It's called, well it's coming up, but in the twiff 519, you guys actually talked about, they did a study where they infected neurons in the cell culture model with Hopi's virus, and the neurons started making abeta protein as a way to fight the virus. So apparently the abeta protein might have some anti-viral activity, so that might explain why they're being made by the neurons. Okay so they've previously shown that you can lately infect these induced neuro stem cell cultures, which means you infect with virus, and then you treat with an antiviral drug, and then you end up having latent DNA in the cells, so you don't have any viral DNA replication, and the viral DNA persists, and you can show that there's no infectious virus produced from these cells. They have, these latently infected human 3D brain tissues have no AD associated phenotypes, as they've previously shown, right? So now we have the main experiment they're going to say ask whether injury can reactivate HSV1 infection, and if it can, whether it can induce AD associated phenotypes, because as we saw with a latently infected model, you don't get any AD associated phenotypes. All right so they first did this in 2D model layer cultures, they have latency established, and then they injure these cells by scratch method and maintain them in culture, and they find that HSV1 lately, in fact the culture is exposed to scratch when demonstrate reactivation of virus and induction of beta and alloy production, which they can see by immunostaining. It was also seen, no beta amyloid is seen in macinfected cultures, right? So just you need virus and the injury there, and they also look at GFAP, and they see substantial upper regulation in response to the injury. Yeah. So Vincent, the establishment of latency, so these researchers gave infected, in fact, to the neurons with HSV1, and then established latency with antiviral, that, you know, doctors give to patients with cold cells, I presume, is that the normal way of establishing latency, or like do humans, when they're infected with HSV1, does the immune system actually cause it to go into latency as well? That's a good question. So normally when you get your first infection with HSV1, you know, it's typically on your lips or nose, and then it goes to the trigeminal ganglia, which is on either side of your face, and there it goes into the neurons and becomes latent. Transcriptional program is shut off. So the latency doesn't establish in the like skin cells. No. Ah, interesting. Only in peripheral ganglia. Okay. And not in the brain, but apparently it could happen in the brain as we're seeing here. Do people know why the neurons are susceptible to latency, but not skin cells, and other cells that also get infected? No, I don't believe so. I've never seen anything that would address that. So the genome in the latently infected cells in the ganglia is completely silent, silent, except for the production of a latency associated transcript lat, which is thought to keep cells in latency. Exactly what that does, we don't know. Is it made so protein or is it just as a no protein? Just RNAs, regulatory RNAs. Okay. So they want to know whether 3D human cultures respond like these monolayers. So they generate 3D human brain tissues. They induce latency. And then they find that human brain tissues infected with latent ages if you want to express higher levels of beta amyloid plaque production as opposed to mock infected samples. And they also found that CHI and 3D tissues induce GFAP expression regardless of infection status. Now CHI being the close-hat injury model. So like. Right. Yeah. When you shake it up. Yeah. And you also see the XSV protein itself. I think that's a protein that they stained for. Like that also comes back up so that it also becomes reactive. The Hopi virus infection reactivates. Yeah. Right. Okay. So then they use this in 3D injury studies. Because they want to initiate trauma that would elicit a response without causing massive destruction. Right. So they use an in vivo rodent model of CCI. And as with CHI, they demonstrate that mild CCI can cause HSV reactivation leading to beta amyloid accumulation in this rodent model. So there is some injury to animals here. Okay. But the common theme is that any injury to the brain in a latent infected brain would actually cause reactivation. Yeah. Yes. Okay. So CHI results in reactivation of latent HSV and the induction of AD associated phenotypes. So what's the role of repetitive injury? So the 3D tissues are generated a lot to mature. They mock or latent intently infect with HSV1. And then they do brain injury. So no detectable levels of UL29, which is a viral protein in cells that had no subsequent injury. It was a marginal increase in UL29 after a single CHI event. But it greater than 20 fold increase in response to triple CHI treatment. It's so striking. They have to cut off the scale bar and make another one because it's such a huge effect. So a single CHI event gives a slight but significant upregulation of beta amyloid, whereas repetitive CHI causes robust induction. And only triply injured, latently, in fact, HSV1, in fact, to sample showed detectable levels of phosphorylated tau. So showing that repetitive concussion like injury on a background of latent HSV1 results in abundant AD associated phenotypes. Right. So that's what they were trying to figure out here essentially. So TBI causes reactivation of latent HSV1 in this 3D brain model. It just as it occurs after secondary affection with VZV. And if the injury is repeated, the damage is much greater than after a single blow. Yeah. It's very curious that this finding is actually quite amazing. If you think about it, because if you. So one of the things that. I don't know. So one of the things that having hopi simplex virus in the brain can cause is. This thing called hopi simplex encephalitis, if you. So I actually don't know what the symptoms are, but it sounds like it's bad. You don't want to get that. And if. So from the previous two of that, you got. That was released over the weekend and also from previous studies. There's some suggestions that both amylobita and also phosphorylated tau might have a. Might have an antiviral role that it plays so that it actually helps neurons survive more in the face of a hopi virus infection. So nowadays, we have a lot of people exploring medication that combats that would target avita protein to help it maybe dissolve better the antibodies against it that we try to help the brain clear it. And I'm guessing there are also drugs trying to block tau phosphorylation just to try to climb down the toxicity. But it sounds like if you. In those cases, if you suffer any sort of TBI, any kind of brain injury, that might actually be quite bad because the brain is actually making these things to try to fight the virus. So there's like very strong implications on how we might want to treat Alzheimer's disease going forward, especially in an increasingly head injury prone world with all the uber, uber, bike delivery people on the street that I see and also myself. It could involve anti-viral treatment. So that's a one thing that they didn't test. So I'm wondering whether from going forward, if someone shows up to the hospital with concussion or with brain injury, do you give anti-viral? So they actually didn't test it in this particular experiment where they. So the test that might be interesting to do is you do the whole thing again. You shake the 3D brain model to give it a close head injury. And then you wait, I don't know, 30 minutes, which is, or maybe an hour, however long it takes an ambulance to take you to the hospital. And then you give anti-viral into this brain culture and see if it actually can block any of these amelot beta and phosphorylation tau. And also even like XSV reactivation because I wonder how. Because it's. I don't know if they know how the brain injury itself causes the increase in XSV. It causes the virus to be reactivated. Right. There's some clue because they actually showed that one of your immune signaling molecule is IL1B. So that's an immune molecule. That's pro-inflammatory, I believe. And that seems to be upregulated when you have a TBI, when you have a head injury, or when you shake up the brain. And if they block it, they can actually block the virus from being reactivated. So kind of paradoxically, the virus being reactivated seems to require a pro-inflammatory. Immune signaling molecule. So I'm not quite sure what the mechanism is. But yeah, it sounds like anti. Like doctors should really. I mean, we should run some trials on giving patients NC viral after kind of head injury to see if it will be a very long-running, very long-running experiment. But I don't know if they can detect. Remember reading the discussion they said they can detect some HSV DNA in CSF, in your cerebral spinal fluid, in just adults in general. So suggesting that is some latent infection, or that latent infection is more common than people thought. Yeah, they say that HSV DNA is far more prevalent in CSF than expected. Yeah, so maybe if they are able to do like a lump of puncture spinal tap on patients, that's head injury to see if that HSV DNA spikes after head injury. And whether anti-viral can make it come back down, it would be. So this is indicating that HSV reactivation occurs in the brain as well as the peripheral nervous system. So that's something we didn't realize before. We thought it was a peripheral nervous system. And when you get herpes in cephalitis, the virus just gets. goes the wrong direction from the peripheral ganglia, right? But here the suggestion is that there can be latency in the brain. And I don't know how you figure out the extent of that, because we have to do biopsies to do that. Yeah, I think people are developing kind of contrast agent dyes, essentially, that would allow you to scan your hamilot plaque in the brain. So maybe you can do a little bit of non-invasive tracking over time. But yeah, it's. It actually is quite optimistic in that it suggests there are ways of maybe helping Alzheimer's not get worse in certain people. So there are people who just has Alzheimer's without ever having a brain injury, of course. Right. And so they note a paper where the risk of Alzheimer's and/or dementia is greater in HSCV1, in fact, individuals in antiviral's decrease this risk. Yeah, actually, I remember when you guys, on twiff, on the previous episode when you were talking about herpesymplex virus and Alzheimer's, you mentioned that our trial was going on with anti-viral and yeah, and Alzheimer's. I wonder if those are kind of promising or not. Yeah, those are overwhelming early onset Alzheimer's, Alzheimer's patients, right? Yeah, it will take a long time before you. So yeah, it takes a long time. You can't be advanced. You have to be pretty early on, and yeah, it's a long-term study. Yeah, they're giving them antivirals and a lot of antivirals, daily. Do you think in. So people with coltol, that gets reactivated every now and then due to stress or due to other reasons. Is that indicative of latent HSCV in the peripheral ganglion that is getting reactivated? And if yes, would that also predict in the brain something might be reactivated? If it's a systemic stressor that the person's going through? I wonder. I suppose it's possible. You could get peripheral reactivation and then the virus goes into the CNS and becomes latent in a certain fraction of people, yeah? But if it's a stressor that would increase maybe into who can one be expression or something, that just in the brain itself could already reactivate a healthy, simplex virus. So you might not need a head injury. You might like other environmental stimuli can might also reactivate HSCV in the brain and that might actually be a contributor to Alzheimer's. No idea. Just guessing. They say that we propose after brain injury whether by infection or mechanical damage, so it doesn't have to be traumatic. It could be an infection. The inflammation induces HSC reactivation in the brain leading to development of AD dementia. So they believe that HSCV one is a major cause of the disease, especially in April E4 carriers. So yeah, they want to know what can we do to mitigate or stop the damage caused by head injury, anti-inflammatory treatment, antiviral treatment, preventing reactivation in the brain and reducing development of AD. It was quite interesting. Very interesting. Just wondering, do you know if analogously, is that word? In people with chickenpox or people who previously had chickenpox, does a skin injury reactivate chickenpox or like some sort of bruising? Let's look it up. I'm guessing it might be more rare because we would have known it by now because so many people have had chickenpox in the past. And general people don't know. Yes, skin injury can reactivate VZV. Oh, okay. So yeah, it's analogous. But it's rare. Okay. Interesting. Yeah, these kind of, these nasty new rochropic latent viruses seem to be causing us a lot of like chronic health issues. Because I remember like Epstein bar virus, which is part of, it's in the herpes greater family, if not mistaken. That seems to be associated with multiple sclerosis, which I think to have also covered a while ago. So yeah, all of these viruses that live inside neurons seem to be really problematic long term. And what's worse is, or like a large majority of us seem to be infected by them. It's just no escape. So we really have to hope for good antiviral or somewhere of combating them. Well, acyclovir is very good. So it's a matter of seeing if it has an effect. They're not many other antivirals because it works so well. But you can't take them every day, right? You have to, like when it when it flares up, when it reactivates, you take them in this trial of early onset Alzheimer's, they were taking them every day. Oh, is that new? Is that no rams every day? Is that no fear of resistance building up in the virus? Or if they don't get to replicate, they don't get to mutate. Well, you know, you can get resistance to acyclovir for sure. It's relatively rare, but it can happen, yeah. And so that's one thing they should be looking at in their study. Yeah, fascinating, very much. Also a little bit, a little bit concerning. But yeah, when I read, when I saw this paper, I remember what you mentioned about the new administration in America, or what have Arcajunia, his, his state of refocusing on chronic disease and defocusing on infectious disease. But I think this paper is a very good illustration of how those two are can be intimacy linked. Yep. So you might not be able to know the course of chronic disease without knowing infectious disease. Yeah. So we need both. We need both this simplified reaction to getting rid of one and favoring the other that doesn't work. All right, that's a twin 57. You can find the show notes at microbe.tv/twins and your questions and comments to [email protected]. And if you like these programs, consider supporting us. Tim Chong is at New York University. Thanks, Tim. Thanks, Vincent. And Vincent Rackenello, you can find me at microbe.tv. You've been listening to this week in neuroscience. Thanks for joining us. We'll be back next month.